[Paper-level Aggregated] PMCID: PMC8688876

Evidence Type(s): Functional

Summary: Mutation: G12 | Summary: The G12 mutation is associated with alterations in the biochemical properties of the GTPase encoded by KRAS, affecting functions such as GTP binding, nucleotide exchange, and distinct vulnerabilities to the enzyme. It is also linked to changes in molecular function, particularly in relation to GAP-mediated hydrolysis and GTP-binding domain activity.

Evidence Type: Functional Mutation: G13 | Summary: The G13 mutation exhibits higher induction with higher variance and is linked to changes in biochemical properties that affect RAF affinity and may influence downstream signaling mechanisms. It is also associated with alterations in molecular function.

Evidence Type: Functional Mutation: Q61 | Summary: The Q61 mutation affects the biochemical properties of the KRAS GTPase, impacting functions such as GTP binding and nucleotide exchange. It is part of the broader distribution of KRAS hotspot variants and is implicated in functional differences related to GTP hydrolysis and signaling pathways.

Evidence Type: Functional Mutation: G12V | Summary: The G12V mutation is specifically noted for having all six biochemical measurements, indicating its significant impact on the functional properties of the KRAS GTPase. Its RAF affinity profile indicates a change in molecular function.

Evidence Type: Functional Mutation: A146T | Summary: The A146T variant is associated with increased GTP binding and is suggested to alter molecular function by modulating GAP binding and changing the probability of locally unfolded conformations, impacting GAP-mediated hydrolysis rates.

Evidence Type: Functional Mutation: A146V | Summary: The A146V mutation is associated with alterations in local stability and may modulate local unfolding, indicating a change in molecular function. It is also predicted to have an intermediate decrease in RAF affinity.

Evidence Type: Functional Mutation: A59T | Summary: The A59T variant has a distinct profile among the mutants, indicating a potential alteration in molecular function. It is predicted to have an intermediate decrease in RAF affinity.

Evidence Type: Functional Mutation: G12A/R | Summary: The G12A/R variant is part of a cluster that shows similarities with other variants, suggesting functional implications and is associated with comparable effects to G12S, implicating it in altering molecular function related to GAP-mediated hydrolysis.

Evidence Type: Functional Mutation: G12D | Summary: The G12D mutation has been shown to have a specific level of downstream activity, indicating an alteration in molecular or biochemical function. It is discussed in the context of conflicting reports regarding its effects, suggesting it may alter molecular function.

Evidence Type: Functional Mutation: G12S | Summary: The G12S variant is indicated to have comparable effects to G12A/R and is involved in altering molecular function related to GAP-mediated hydrolysis. It is predicted to have a decreased RAF affinity.

Evidence Type: Functional Mutation: G13C | Summary: The G13C variant is part of a group of variants that relate to local stability and may affect local unfolding, suggesting a functional impact. It is also predicted to have RAF affinity comparable to wild-type, indicating no significant alteration in molecular function.

Evidence Type: Functional Mutation: G13V | Summary: The G13V mutation is included in a cluster of variants that influence local stability and local unfolding probabilities, indicating a functional alteration. It is also indicated to have a significant effect on GAP-mediated hydrolysis and is predicted to have an intermediate decrease in RAF affinity.

Evidence Type: Functional Mutation: K117N | Summary: The K117N mutation is identified as a non-hotspot variant that may affect local stability and local unfolding, suggesting a change in molecular function. It is noted to have comparable effects to G13D and Q61H, indicating a potential alteration in molecular function.

Evidence Type: Functional Mutation: T74 | Summary: The T74 mutation is associated with alterations in the biochemical properties of the KRAS GTPase, influencing functions like GTP binding and nucleotide exchange. The T74P variant alters RAF affinity, indicating a change in molecular function related to tumor development.

Evidence Type: Functional Mutation: R164Q | Summary: The R164Q variant behaves like wild-type KRAS, indicating a potential alteration in molecular function. Its RAF affinity profile suggests it alters molecular function in a manner similar to other variants.

Evidence Type: Functional Mutation: Q22K | Summary: The Q22K variant is associated with increased GTP binding and shows a similar RAF affinity profile to other variants, suggesting an alteration in molecular function.

Evidence Type: Functional Mutation: L19F | Summary: The L19F variant shows similarities with hotspot variants, suggesting functional relevance. It is compared to G13D and Q61H, indicating a potential alteration in molecular function and is predicted to have RAF affinity comparable to wild-type.

Evidence Type: Functional Mutation: Q61H | Summary: The Q61H variant is associated with increased GTP binding and is mentioned in relation to its effects on GAP-mediated hydrolysis, suggesting it may alter molecular function. It shows relatively smaller changes in RAF affinity, suggesting a minor alteration in molecular function.

Evidence Type: Functional Mutation: Q61L/P | Summary: The Q61L/P variant is included in a cluster that suggests functional implications.

Evidence Type: Functional Mutation: Q61R | Summary: The Q61R variant shows a distinct RAF affinity profile, indicating a change in molecular function and is predicted to have RAF affinity comparable to wild-type, indicating no significant alteration in molecular function.

Gene→Variant (gene-first): KRAS(3845):G12 KRAS(3845):G13 KRAS(3845):Q61 KRAS(3845):G12V KRAS(3845):A146T HRAS(3265):A146V HRAS(3265):A59T KRAS(3845):G12A/R KRAS(3845):G12D KRAS(3845):G12S KRAS(3845):G13C HRAS(3265):G13V KRAS(3845):K117N ZHX2(22882):T74 KRAS(3845):R164Q KRAS(3845):Q22K KRAS(3845):L19F KRAS(3845):Q61H KRAS(3845):Q61L/P NRAS(4893):Q61R

Genes: KRAS(3845) HRAS(3265) ZHX2(22882) NRAS(4893)

Variants: G12 G13 Q61 G12V A146T A146V A59T G12A/R G12D G12S G13C G13V K117N T74 R164Q Q22K L19F Q61H Q61L/P Q61R

[Paragraph-level] PMCID: PMC8688876 Section: RESULTS PassageIndex: 20

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: G12 | Summary: The G12 variant is associated with alterations in molecular function, particularly in relation to GAP-mediated hydrolysis and GTP-binding domain activity. Evidence Type: Functional | Mutation: G13 | Summary: The G13 variant exhibits changes in biochemical properties that affect RAF affinity and may influence downstream signaling mechanisms. Evidence Type: Functional | Mutation: Q61 | Summary: The Q61 variant is implicated in functional differences related to GTP hydrolysis and signaling pathways, as indicated by its interaction with RAS proteins.

Gene→Variant (gene-first): 3845:G12 3845:G13 3845:Q61

Genes: 3845

Variants: G12 G13 Q61

[Paragraph-level] PMCID: PMC8688876 Section: RESULTS PassageIndex: 19

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: G12 | Summary: The G12 mutation is associated with distinct vulnerabilities to the enzyme, indicating that it alters molecular or biochemical function. Evidence Type: Functional | Mutation: G12C | Summary: The G12C mutation conveys a different level of downstream activity, suggesting it alters molecular or biochemical function. Evidence Type: Functional | Mutation: G12D | Summary: The G12D mutation has been shown to have a specific level of downstream activity, indicating an alteration in molecular or biochemical function. Evidence Type: Functional | Mutation: G13 | Summary: The G13 mutation exhibits higher induction with higher variance, suggesting it alters molecular or biochemical function. Evidence Type: Functional | Mutation: Q61 | Summary: The Q61 mutation is part of the broader distribution of KRAS hotspot variants, indicating it alters molecular or biochemical function.

Gene→Variant (gene-first): 3845:G12 3845:G12C 3845:G12C/D 3845:G12D 3845:G13 3845:Q61

Genes: 3845

Variants: G12 G12C G12C/D G12D G13 Q61

[Paragraph-level] PMCID: PMC8688876 Section: RESULTS PassageIndex: 16

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: G12S | Summary: G12S is predicted to have a decreased RAF affinity, indicating an alteration in molecular function. Evidence Type: Functional | Mutation: G13V | Summary: G13V is predicted to have an intermediate decrease in RAF affinity, suggesting a change in molecular function. Evidence Type: Functional | Mutation: Q61P | Summary: Q61P is predicted to have an intermediate decrease in RAF affinity, indicating an alteration in molecular function. Evidence Type: Functional | Mutation: A59T | Summary: A59T is predicted to have an intermediate decrease in RAF affinity, suggesting a change in molecular function. Evidence Type: Functional | Mutation: A146V | Summary: A146V is predicted to have an intermediate decrease in RAF affinity, indicating an alteration in molecular function. Evidence Type: Functional | Mutation: Q61H | Summary: Q61H shows relatively smaller changes in RAF affinity, suggesting a minor alteration in molecular function. Evidence Type: Functional | Mutation: A18D | Summary: A18D shows relatively smaller changes in RAF affinity, indicating a minor alteration in molecular function. Evidence Type: Functional | Mutation: Q22K | Summary: Q22K shows relatively smaller changes in RAF affinity, suggesting a minor alteration in molecular function. Evidence Type: Functional | Mutation: G13C | Summary: G13C is predicted to have RAF affinity comparable to WT, indicating no significant alteration in molecular function. Evidence Type: Functional | Mutation: G13S | Summary: G13S is predicted to have RAF affinity comparable to WT, indicating no significant alteration in molecular function. Evidence Type: Functional | Mutation: Q61R | Summary: Q61R is predicted to have RAF affinity comparable to WT, indicating no significant alteration in molecular function. Evidence Type: Functional | Mutation: L19F | Summary: L19F is predicted to have RAF affinity comparable to WT, indicating no significant alteration in molecular function. Evidence Type: Functional | Mutation: T74P | Summary: T74P is predicted to have RAF affinity comparable to WT, indicating no significant alteration in molecular function. Evidence Type: Functional | Mutation: K117N | Summary: K117N is predicted to have RAF affinity comparable to WT, indicating no significant alteration in molecular function. Evidence Type: Functional | Mutation: R164Q | Summary: R164Q is predicted to have RAF affinity comparable to WT, indicating no significant alteration in molecular function.

Gene→Variant (gene-first): 3265:A146V 673:A18D 3265:A59T 3845:G12 3845:G12S 3845:G13C 3265:G13V 3845:K117N 3845:L19F 3845:Q22K 3845:Q61H 3845:Q61P 4893:Q61R 3845:R164Q 22882:T74P

Genes: 3265 673 3845 4893 22882

Variants: A146V A18D A59T G12 G12S G13C G13V K117N L19F Q22K Q61H Q61P Q61R R164Q T74P

[Paragraph-level] PMCID: PMC8688876 Section: RESULTS PassageIndex: 15

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: T74P | Summary: The T74P variant alters RAF affinity, indicating a change in molecular function related to tumor development. Evidence Type: Functional | Mutation: R164Q | Summary: The R164Q variant resembles hotspot variants in terms of RAF affinity, suggesting it alters molecular function. Evidence Type: Functional | Mutation: L19F | Summary: The L19F variant shows a pattern of RAF affinity similar to other variants, indicating a change in molecular function. Evidence Type: Functional | Mutation: K117N | Summary: The K117N variant's RAF affinity profile suggests it alters molecular function in a manner similar to other variants. Evidence Type: Functional | Mutation: A18D | Summary: The A18D variant resembles other variants in RAF affinity, indicating a change in molecular function. Evidence Type: Functional | Mutation: Q22K | Summary: The Q22K variant shows a similar RAF affinity profile to other variants, suggesting an alteration in molecular function. Evidence Type: Functional | Mutation: A146T | Summary: The A146T variant's RAF affinity profile indicates a change in molecular function related to tumor development. Evidence Type: Functional | Mutation: G12R | Summary: The G12R variant clusters with other variants in terms of RAF affinity, suggesting an alteration in molecular function. Evidence Type: Functional | Mutation: A59T | Summary: The A59T variant's clustering with other variants indicates a change in molecular function related to RAF affinity. Evidence Type: Functional | Mutation: A146V | Summary: The A146V variant's RAF affinity profile suggests it alters molecular function in a manner similar to other variants. Evidence Type: Functional | Mutation: G12C | Summary: The G12C variant shows a distinct RAF affinity profile, indicating a change in molecular function. Evidence Type: Functional | Mutation: G12C/D | Summary: The G12C/D variant's RAF affinity profile suggests an alteration in molecular function. Evidence Type: Functional | Mutation: G12V | Summary: The G12V variant's RAF affinity profile indicates a change in molecular function. Evidence Type: Functional | Mutation: G12S | Summary: The G12S variant shows a distinct RAF affinity profile, indicating a change in molecular function. Evidence Type: Functional | Mutation: Q61H | Summary: The Q61H variant's RAF affinity profile suggests it alters molecular function. Evidence Type: Functional | Mutation: Q61L | Summary: The Q61L variant shows a similar RAF affinity profile to other variants, indicating an alteration in molecular function. Evidence Type: Functional | Mutation: Q61P | Summary: The Q61P variant's RAF affinity profile indicates a change in molecular function. Evidence Type: Functional | Mutation: Q61R | Summary: The Q61R variant shows a distinct RAF affinity profile, indicating a change in molecular function. Evidence Type: Functional | Mutation: G13C | Summary: The G13C variant's RAF affinity profile suggests it alters molecular function. Evidence Type: Functional | Mutation: G13D | Summary: The G13D variant shows a similar RAF affinity profile to other variants, indicating an alteration in molecular function. Evidence Type: Functional | Mutation: G13V | Summary: The G13V variant's RAF affinity profile indicates a change in molecular function. Evidence Type: Functional | Mutation: G13S | Summary: The G13S variant shows a distinct RAF affinity profile, indicating a change in molecular function.

Gene→Variant (gene-first): 3845:A146T 3265:A146V 673:A18D 3265:A59T 3845:G12C 3845:G12C/D 3845:G12R 3845:G13C/D 3265:G13V 3845:K117N 3845:L19F 3845:Q22K 3845:Q61H/L 3845:Q61P 4893:Q61R 3845:R164Q 22882:T74P 22882:V/A

Genes: 3845 3265 673 4893 22882

Variants: A146T A146V A18D A59T G12C G12C/D G12R G13C/D G13V K117N L19F Q22K Q61H/L Q61P Q61R R164Q T74P V/A

[Paragraph-level] PMCID: PMC8688876 Section: RESULTS PassageIndex: 13

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: A146T | Summary: A146T is suggested to alter molecular function by modulating GAP binding and changing the probability of locally unfolded conformations, impacting GAP-mediated hydrolysis rates. Evidence Type: Functional | Mutation: A146V | Summary: A146V is indicated to affect molecular function, as it associates with higher relative GAP-mediated hydrolysis compared to A146T. Evidence Type: Functional | Mutation: A59T | Summary: A59T is mentioned in the context of comparing its effects to G13D and Q61H, suggesting it may alter molecular function related to GAP-mediated hydrolysis. Evidence Type: Functional | Mutation: K117N | Summary: K117N is noted to have comparable effects to G13D and Q61H, indicating a potential alteration in molecular function. Evidence Type: Functional | Mutation: G12A/R | Summary: G12A/R is associated with comparable effects to G12S and is implicated in altering molecular function related to GAP-mediated hydrolysis. Evidence Type: Functional | Mutation: G12D | Summary: G12D is discussed in the context of conflicting reports regarding its effects, suggesting it may alter molecular function. Evidence Type: Functional | Mutation: G12S | Summary: G12S is indicated to have comparable effects to G12A/R and is involved in altering molecular function related to GAP-mediated hydrolysis. Evidence Type: Functional | Mutation: G13C | Summary: G13C is suggested to have a relatively lower effect compared to G13V, indicating a potential alteration in molecular function. Evidence Type: Functional | Mutation: G13D | Summary: G13D is mentioned in the context of its effects on GAP-mediated hydrolysis, suggesting it may alter molecular function. Evidence Type: Functional | Mutation: G13V | Summary: G13V is indicated to have a significant effect on GAP-mediated hydrolysis, suggesting an alteration in molecular function. Evidence Type: Functional | Mutation: L19F | Summary: L19F is compared to G13D and Q61H, indicating a potential alteration in molecular function. Evidence Type: Functional | Mutation: Q61H | Summary: Q61H is mentioned in relation to its effects on GAP-mediated hydrolysis, suggesting it may alter molecular function.

Gene→Variant (gene-first): 3845:A146T 3265:A146V 673:A18D 3265:A59T 3845:G12A/R 3845:G12D 3845:G12S 3845:G13C 3845:G13D 3265:G13V 3845:K117N 3845:L19F 3845:Q22K 3845:Q61H 22882:T74P

Genes: 3845 3265 673 22882

Variants: A146T A146V A18D A59T G12A/R G12D G12S G13C G13D G13V K117N L19F Q22K Q61H T74P

[Paragraph-level] PMCID: PMC8688876 Section: RESULTS PassageIndex: 12

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: A146V | Summary: The A146V mutation is associated with alterations in local stability and may modulate local unfolding, indicating a change in molecular function. Evidence Type: Functional | Mutation: G13C | Summary: The G13C mutation is part of a group of variants that relate to local stability and may affect local unfolding, suggesting a functional impact. Evidence Type: Functional | Mutation: G13V | Summary: The G13V mutation is included in a cluster of variants that influence local stability and local unfolding probabilities, indicating a functional alteration. Evidence Type: Functional | Mutation: K117N | Summary: The K117N mutation is identified as a non-hotspot variant that may affect local stability and local unfolding, suggesting a change in molecular function.

Gene→Variant (gene-first): 3265:A146V 3845:G13C 3265:G13V 3845:K117N

Genes: 3265 3845

Variants: A146V G13C G13V K117N

[Paragraph-level] PMCID: PMC8688876 Section: RESULTS PassageIndex: 5

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: A146T | Summary: The variant A146T is associated with increased GTP binding, indicating an alteration in molecular function. Evidence Type: Functional | Mutation: A146T/V | Summary: The variant A146T/V shows differences in behavior compared to hotspot variants, suggesting a functional impact on molecular activity. Evidence Type: Functional | Mutation: A59T | Summary: The variant A59T has a distinct profile among the mutants, indicating a potential alteration in molecular function. Evidence Type: Functional | Mutation: G12A/R | Summary: The G12A/R variant is part of a cluster that shows similarities with other variants, suggesting functional implications. Evidence Type: Functional | Mutation: G12A/R/S | Summary: The G12A/R/S variant is included in a cluster with other variants, indicating potential functional relevance. Evidence Type: Functional | Mutation: G12V/D | Summary: The G12V/D variant is associated with increased GTP binding, suggesting an alteration in molecular function. Evidence Type: Functional | Mutation: G13C | Summary: The G13C variant is part of a cluster that indicates functional similarities with other variants. Evidence Type: Functional | Mutation: G13V/D | Summary: The G13V/D variant is included in a cluster that suggests functional implications. Evidence Type: Functional | Mutation: K177N | Summary: The K177N variant is associated with increased GTP binding, indicating a potential alteration in molecular function. Evidence Type: Functional | Mutation: L19F | Summary: The L19F variant shows similarities with hotspot variants, suggesting functional relevance. Evidence Type: Functional | Mutation: Q22K | Summary: The Q22K variant is associated with increased GTP binding, indicating an alteration in molecular function. Evidence Type: Functional | Mutation: Q61 | Summary: The Q61 variant is part of a cluster that indicates functional implications. Evidence Type: Functional | Mutation: Q61H | Summary: The Q61H variant is associated with increased GTP binding, suggesting a potential alteration in molecular function. Evidence Type: Functional | Mutation: Q61L/P | Summary: The Q61L/P variant is included in a cluster that suggests functional implications. Evidence Type: Functional | Mutation: R164Q | Summary: The R164Q variant behaves like wild-type KRAS, indicating a potential alteration in molecular function. Evidence Type: Functional | Mutation: T74P | Summary: The T74P variant shows similarities with hotspot variants, suggesting functional relevance.

Gene→Variant (gene-first): 3845:A146T 3845:A146T/V 3265:A59T 3845:G12A/R 3845:G12A/R/S 3845:G12V/D 3845:G13C 3845:G13V/D 673:K177N 3845:L19F 3845:Q22K 3845:Q61 3845:Q61H 3845:Q61L/P 3845:R164Q 22882:T74P

Genes: 3845 3265 673 22882

Variants: A146T A146T/V A59T G12A/R G12A/R/S G12V/D G13C G13V/D K177N L19F Q22K Q61 Q61H Q61L/P R164Q T74P

[Paragraph-level] PMCID: PMC8688876 Section: RESULTS PassageIndex: 4

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: G12 | Summary: The G12 mutation is associated with alterations in the biochemical properties of the GTPase encoded by KRAS, affecting functions such as GTP binding and nucleotide exchange. Evidence Type: Functional | Mutation: G13 | Summary: The G13 mutation is linked to changes in the biochemical properties of the KRAS GTPase, influencing aspects like GTP binding and nucleotide exchange. Evidence Type: Functional | Mutation: Q61 | Summary: The Q61 mutation affects the biochemical properties of the KRAS GTPase, impacting functions such as GTP binding and nucleotide exchange. Evidence Type: Functional | Mutation: T74 | Summary: The T74 mutation is associated with alterations in the biochemical properties of the KRAS GTPase, influencing functions like GTP binding and nucleotide exchange. Evidence Type: Functional | Mutation: G12V | Summary: The G12V mutation is specifically noted for having all six biochemical measurements, indicating its significant impact on the functional properties of the KRAS GTPase.

Gene→Variant (gene-first): 3845:G12 3845:G12V 3845:G13 3845:Q61 22882:T74

Genes: 3845 22882

Variants: G12 G12V G13 Q61 T74

[Paper-level Aggregated] PMCID: PMC8688876

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

Justification: Functional: The text discusses the biochemical properties of KRAS variants, including their effects on GTP binding, hydrolysis rates, and RAF affinity, indicating that these variants have functional consequences on the protein's activity. Oncogenic: The mention of KRAS variants, particularly hotspot mutations, in the context of their roles in cancer suggests that these mutations are associated with oncogenic potential, as they alter the protein's function in a way that can contribute to tumorigenesis. Predictive: The analysis includes predictions of RAF affinity and GAP-mediated hydrolysis rates for various KRAS variants, indicating that the data can be used to predict the functional impact of these mutations on KRAS activity. Prognostic: The study's findings on the varying effects of different KRAS mutations on downstream signaling and their correlation with pERK levels suggest that these variants may have prognostic implications in cancer outcomes.

Gene→Variant (gene-first): KRAS(3845):A146T KRAS(3845):A146T/V HRAS(3265):A59T KRAS(3845):G12A/R KRAS(3845):G12A/R/S KRAS(3845):G12V/D KRAS(3845):G13C KRAS(3845):G13V/D BRAF(673):K177N KRAS(3845):L19F KRAS(3845):Q22K KRAS(3845):Q61 KRAS(3845):Q61H KRAS(3845):Q61L/P KRAS(3845):R164Q ZHX2(22882):T74P HRAS(3265):A146V BRAF(673):A18D KRAS(3845):G12D KRAS(3845):G12S KRAS(3845):G13D HRAS(3265):G13V KRAS(3845):K117N KRAS(3845):G12C KRAS(3845):G12C/D KRAS(3845):G12R KRAS(3845):G13C/D KRAS(3845):Q61H/L KRAS(3845):Q61P NRAS(4893):Q61R ZHX2(22882):V/A KRAS(3845):G12 KRAS(3845):G13 KRAS(3845):G12V ZHX2(22882):T74

Genes: KRAS(3845) HRAS(3265) BRAF(673) ZHX2(22882) NRAS(4893)

Variants: A146T A146T/V A59T G12A/R G12A/R/S G12V/D G13C G13V/D K177N L19F Q22K Q61 Q61H Q61L/P R164Q T74P A146V A18D G12D G12S G13D G13V K117N G12C G12C/D G12R G13C/D Q61H/L Q61P Q61R V/A G12 G13 G12V T74

[Paragraph-level] PMCID: PMC8688876 Section: RESULTS PassageIndex: 20

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how specific amino acid substitutions at G12, G13, and Q61 alter biochemical properties and mechanisms across RAS proteins, indicating a change in molecular function related to GTP hydrolysis and downstream signaling. Oncogenic: The mention of hotspot variants and their clustering patterns suggests that these somatic variants contribute to tumor development or progression, particularly in the context of their distinct biochemical properties and disease incidence.

Gene→Variant (gene-first): 3845:G12 3845:G13 3845:Q61

Genes: 3845

Variants: G12 G13 Q61

[Paragraph-level] PMCID: PMC8688876 Section: RESULTS PassageIndex: 19

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how different KRAS mutations, including G12C/D and G12D, affect downstream activity and enzyme function, as demonstrated by Western blot analyses measuring pERK levels. Oncogenic: The mention of KRAS hotspot variants and their distinct effects on downstream signaling suggests that these somatic mutations contribute to tumor development or progression.

Gene→Variant (gene-first): 3845:G12 3845:G12C 3845:G12C/D 3845:G12D 3845:G13 3845:Q61

Genes: 3845

Variants: G12 G12C G12C/D G12D G13 Q61

[Paragraph-level] PMCID: PMC8688876 Section: RESULTS PassageIndex: 16

Evidence Type(s): Functional, Predictive

Justification: Functional: The passage discusses how specific amino acid substitutions affect RAF affinity, indicating that these variants alter molecular function related to protein interactions. Predictive: The passage predicts changes in RAF affinity for various variants, suggesting a correlation with potential therapeutic responses or resistance based on their affinity levels.

Gene→Variant (gene-first): 3265:A146V 673:A18D 3265:A59T 3845:G12 3845:G12S 3845:G13C 3265:G13V 3845:K117N 3845:L19F 3845:Q22K 3845:Q61H 3845:Q61P 4893:Q61R 3845:R164Q 22882:T74P

Genes: 3265 673 3845 4893 22882

Variants: A146V A18D A59T G12 G12S G13C G13V K117N L19F Q22K Q61H Q61P Q61R R164Q T74P

[Paragraph-level] PMCID: PMC8688876 Section: RESULTS PassageIndex: 15

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the KRAS variants alter RAF affinity, indicating that these variants affect molecular function, specifically in relation to protein interactions and binding properties. Oncogenic: The context of the variants being associated with RAF affinity suggests a role in tumor development or progression, as RAF is a key component in signaling pathways that drive cancer.

Gene→Variant (gene-first): 3845:A146T 3265:A146V 673:A18D 3265:A59T 3845:G12C 3845:G12C/D 3845:G12R 3845:G13C/D 3265:G13V 3845:K117N 3845:L19F 3845:Q22K 3845:Q61H/L 3845:Q61P 4893:Q61R 3845:R164Q 22882:T74P 22882:V/A

Genes: 3845 3265 673 4893 22882

Variants: A146T A146V A18D A59T G12C G12C/D G12R G13C/D G13V K117N L19F Q22K Q61H/L Q61P Q61R R164Q T74P V/A

[Paragraph-level] PMCID: PMC8688876 Section: RESULTS PassageIndex: 13

Evidence Type(s): Functional, Predictive, Oncogenic

Justification: Functional: The passage discusses how mutated KRAS proteins may alter GAP binding and change GAP-mediated hydrolysis rates, indicating that the variants affect molecular function. Predictive: The analysis provides a probability density distribution and suggests that the variants can predict relative levels for mutations based on their GAP-mediated hydrolysis rates, indicating a correlation with functional outcomes. Oncogenic: The context of the variants being associated with cancer and their effects on GAP-mediated hydrolysis suggests that these somatic variants contribute to tumor development or progression.

Gene→Variant (gene-first): 3845:A146T 3265:A146V 673:A18D 3265:A59T 3845:G12A/R 3845:G12D 3845:G12S 3845:G13C 3845:G13D 3265:G13V 3845:K117N 3845:L19F 3845:Q22K 3845:Q61H 22882:T74P

Genes: 3845 3265 673 22882

Variants: A146T A146V A18D A59T G12A/R G12D G12S G13C G13D G13V K117N L19F Q22K Q61H T74P

[Paragraph-level] PMCID: PMC8688876 Section: RESULTS PassageIndex: 12

Evidence Type(s): Functional

Justification: Functional: The passage discusses how mutations, including G13C, A146V, K117N, and G13V, alter local stability and modulate local unfolding, indicating a change in molecular function related to the hydrolysis rate.

Gene→Variant (gene-first): 3265:A146V 3845:G13C 3265:G13V 3845:K117N

Genes: 3265 3845

Variants: A146V G13C G13V K117N

[Paragraph-level] PMCID: PMC8688876 Section: RESULTS PassageIndex: 5

Evidence Type(s): Functional, Diagnostic

Justification: Functional: The passage discusses how various KRAS variants, including both hotspot and non-hotspot mutations, exhibit distinct profiles and behaviors based on experimental measurements, indicating that these variants alter molecular or biochemical function. Diagnostic: The mention of clustering variants and their association with specific profiles suggests that these variants can be used to classify or define differences in behavior, which aligns with diagnostic evidence.

Gene→Variant (gene-first): 3845:A146T 3845:A146T/V 3265:A59T 3845:G12A/R 3845:G12A/R/S 3845:G12V/D 3845:G13C 3845:G13V/D 673:K177N 3845:L19F 3845:Q22K 3845:Q61 3845:Q61H 3845:Q61L/P 3845:R164Q 22882:T74P

Genes: 3845 3265 673 22882

Variants: A146T A146T/V A59T G12A/R G12A/R/S G12V/D G13C G13V/D K177N L19F Q22K Q61 Q61H Q61L/P R164Q T74P

[Paragraph-level] PMCID: PMC8688876 Section: RESULTS PassageIndex: 4

Evidence Type(s): Functional

Justification: Functional: The passage discusses how various KRAS variants, including G12, G12V, G13, Q61, and T74, affect biochemical properties such as GTP binding, nucleotide exchange, and hydrolysis, indicating that these variants alter molecular or biochemical function.

Gene→Variant (gene-first): 3845:G12 3845:G12V 3845:G13 3845:Q61 22882:T74

Genes: 3845 22882

Variants: G12 G12V G13 Q61 T74

[Paragraph-level] PMCID: PMC8688876 Section: RESULTS PassageIndex: 20

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how specific amino acid substitutions at G12, G13, and Q61 alter biochemical properties and mechanisms across RAS proteins, indicating a change in molecular function related to GTP hydrolysis and downstream signaling. Oncogenic: The mention of hotspot variants and their clustering patterns suggests that these somatic variants contribute to tumor development or progression, particularly in the context of their distinct biochemical properties and disease incidence.

Gene→Variant (gene-first): 3845:G12 3845:G13 3845:Q61

Genes: 3845

Variants: G12 G13 Q61

[Paragraph-level] PMCID: PMC8688876 Section: RESULTS PassageIndex: 19

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how different KRAS mutations, including G12C/D and G12D, affect downstream activity and enzyme function, as demonstrated by Western blot analyses measuring pERK levels. Oncogenic: The mention of KRAS hotspot variants and their distinct effects on downstream signaling suggests that these somatic mutations contribute to tumor development or progression.

Gene→Variant (gene-first): 3845:G12 3845:G12C 3845:G12C/D 3845:G12D 3845:G13 3845:Q61

Genes: 3845

Variants: G12 G12C G12C/D G12D G13 Q61

[Paragraph-level] PMCID: PMC8688876 Section: RESULTS PassageIndex: 16

Evidence Type(s): Functional, Predictive

Justification: Functional: The passage discusses how specific amino acid substitutions affect RAF affinity, indicating that these variants alter molecular function related to protein interactions. Predictive: The passage predicts changes in RAF affinity for various variants, suggesting a correlation with potential therapeutic responses or resistance based on their affinity levels.

Gene→Variant (gene-first): 3265:A146V 673:A18D 3265:A59T 3845:G12 3845:G12S 3845:G13C 3265:G13V 3845:K117N 3845:L19F 3845:Q22K 3845:Q61H 3845:Q61P 4893:Q61R 3845:R164Q 22882:T74P

Genes: 3265 673 3845 4893 22882

Variants: A146V A18D A59T G12 G12S G13C G13V K117N L19F Q22K Q61H Q61P Q61R R164Q T74P

[Paragraph-level] PMCID: PMC8688876 Section: RESULTS PassageIndex: 15

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the KRAS variants alter RAF affinity, indicating that these variants affect molecular function, specifically in relation to protein interactions and binding properties. Oncogenic: The context of the variants being associated with RAF affinity suggests a role in tumor development or progression, as RAF is a key component in signaling pathways that drive cancer.

Gene→Variant (gene-first): 3845:A146T 3265:A146V 673:A18D 3265:A59T 3845:G12C 3845:G12C/D 3845:G12R 3845:G13C/D 3265:G13V 3845:K117N 3845:L19F 3845:Q22K 3845:Q61H/L 3845:Q61P 4893:Q61R 3845:R164Q 22882:T74P 22882:V/A

Genes: 3845 3265 673 4893 22882

Variants: A146T A146V A18D A59T G12C G12C/D G12R G13C/D G13V K117N L19F Q22K Q61H/L Q61P Q61R R164Q T74P V/A

[Paragraph-level] PMCID: PMC8688876 Section: RESULTS PassageIndex: 13

Evidence Type(s): Functional, Predictive, Oncogenic

Justification: Functional: The passage discusses how mutated KRAS proteins may alter GAP binding and change GAP-mediated hydrolysis rates, indicating that the variants affect molecular function. Predictive: The analysis provides a probability density distribution and suggests that the variants can predict relative levels for mutations based on their GAP-mediated hydrolysis rates, indicating a correlation with functional outcomes. Oncogenic: The context of the variants being associated with cancer and their effects on GAP-mediated hydrolysis suggests that these somatic variants contribute to tumor development or progression.

Gene→Variant (gene-first): 3845:A146T 3265:A146V 673:A18D 3265:A59T 3845:G12A/R 3845:G12D 3845:G12S 3845:G13C 3845:G13D 3265:G13V 3845:K117N 3845:L19F 3845:Q22K 3845:Q61H 22882:T74P

Genes: 3845 3265 673 22882

Variants: A146T A146V A18D A59T G12A/R G12D G12S G13C G13D G13V K117N L19F Q22K Q61H T74P

[Paragraph-level] PMCID: PMC8688876 Section: RESULTS PassageIndex: 12

Evidence Type(s): Functional

Justification: Functional: The passage discusses how mutations, including G13C, A146V, K117N, and G13V, alter local stability and modulate local unfolding, indicating a change in molecular function related to the hydrolysis rate.

Gene→Variant (gene-first): 3265:A146V 3845:G13C 3265:G13V 3845:K117N

Genes: 3265 3845

Variants: A146V G13C G13V K117N

[Paragraph-level] PMCID: PMC8688876 Section: RESULTS PassageIndex: 5

Evidence Type(s): Functional, Diagnostic

Justification: Functional: The passage discusses how various KRAS variants, including both hotspot and non-hotspot mutations, exhibit distinct profiles and behaviors based on experimental measurements, indicating that these variants alter molecular or biochemical function. Diagnostic: The mention of clustering variants and their association with specific profiles suggests that these variants can be used to classify or define differences in behavior, which aligns with diagnostic evidence.

Gene→Variant (gene-first): 3845:A146T 3845:A146T/V 3265:A59T 3845:G12A/R 3845:G12A/R/S 3845:G12V/D 3845:G13C 3845:G13V/D 673:K177N 3845:L19F 3845:Q22K 3845:Q61 3845:Q61H 3845:Q61L/P 3845:R164Q 22882:T74P

Genes: 3845 3265 673 22882

Variants: A146T A146T/V A59T G12A/R G12A/R/S G12V/D G13C G13V/D K177N L19F Q22K Q61 Q61H Q61L/P R164Q T74P

[Paragraph-level] PMCID: PMC8688876 Section: RESULTS PassageIndex: 4

Evidence Type(s): Functional

Justification: Functional: The passage discusses how various KRAS variants, including G12, G12V, G13, Q61, and T74, affect biochemical properties such as GTP binding, nucleotide exchange, and hydrolysis, indicating that these variants alter molecular or biochemical function.

Gene→Variant (gene-first): 3845:G12 3845:G12V 3845:G13 3845:Q61 22882:T74

Genes: 3845 22882

Variants: G12 G12V G13 Q61 T74