CHK2 p.R474C Protein Is Poorly Activated in the Cell upon DNA Damage
[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
The tertiary structure of FCGRT-immunoglobulin Fc fragment complex was determined. p.R210 contacts the carboxyl terminus of the immunoglobulin Fc fragment. Although there is a salt bridge between p.R210 and the Fc fragme
[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
Second, we examined how the amino acid substitutions affect the tertiary structure of the proteins. The tertiary structure of the inactive CHK2 homodimer (PDB code: 3i6w) is shown in Figure 4B. p.R474 is located away fro
[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
First, the effects of these missense variants were predicted using the Variant Effect Predictor at Ensembl, for which SIFT (Sorting Intolerant from Tolerant) and PolyPhen (Polymorphism Phenotyping) are used. Three varian
[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
The female patient, FL2, was 6 years older than the male patient. At the age of 38, she was diagnosed with uterine myoma and developed multiple primary lung cancer at the age of 60 with no history of smoking. Three prima
[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
IDH1 R132H and ATRX KO have similar levels of PARP inhibitor sensitivity.
[Paragraph-level] PMCID: PMC8203843 Section: ABSTRACT PassageIndex: 4
Evidence Type(s): Predictive
Justification: Predictive: The passage indicates that IDH1 R132H is associated with sensitivity to PARP inhibitors, which correlates the variant with a specific therapy response.
Gene→Variant (gene-first): 3417:R132H
Genes: 3417
Variants: R132H
FLT3 mutations are the most frequently identified genetic alterations in acute myeloid leukemia (AML) and are associated with poor prognosis. Multiple FLT3 inhibitors are in various stages of clinical evaluation. However
[Paragraph-level] PMCID: PMC8255005 Section: ABSTRACT PassageIndex: 1
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the resistance of FLT3 mutations, specifically F691L, to FLT3 inhibitors and highlights the efficacy of KX2-391 in overcoming this resistance, indicating a correlation with treatment response. Oncogenic: The FLT3 mutations, including D835 and F691, are described as contributing to tumor development and progression in acute myeloid leukemia (AML), which supports their classification as oncogenic variants.
Gene→Variant (gene-first): 2322:D835 2322:D835Y 2322:F691 2322:F691L
Genes: 2322
Variants: D835 D835Y F691 F691L
We studied 47 glioblastomas (WHO grade IV). Heterozygous mutations of IDH1 were found in 6/47 tumours (12%). All 6 mutations were single base substitutions c.395G>A occurring at residue R132, resulting in an arginine to
[Paragraph-level] PMCID: PMC3100313 Section: RESULTS PassageIndex: 2
Evidence Type(s): Diagnostic, Oncogenic
Justification: Diagnostic: The passage discusses the frequency of heterozygous mutations of IDH1, specifically the c.395G>A variant, in glioblastomas, indicating its association with this disease subtype. Oncogenic: The presence of the IDH1 mutation (p.R132H) in glioblastomas suggests that this somatic variant contributes to tumor development or progression.
Gene→Variant (gene-first): 728294:R132 79944:arginine to histidine 728294:c.395G>A 3417:p.R132H
Genes: 728294 79944 3417
Variants: R132 arginine to histidine c.395G>A p.R132H
To get a deeper insight into the molecular characteristics of this group, we analyzed next-generation sequencing results from 17 cases. Seven cases were analyzed using the Heidelberg 130 gene panel, six cases were sequen
[Paragraph-level] PMCID: PMC7785563 Section: RESULTS PassageIndex: 12
Evidence Type(s): Diagnostic, Oncogenic
Justification: Diagnostic: The passage indicates that 90% of the cases harbored IDH1-R132H mutations, which are associated with conventional supratentorial IDH-mutant astrocytomas, suggesting a role in defining or classifying the disease. Oncogenic: The presence of IDH1-R132H mutations in the tumors suggests that this somatic variant contributes to tumor development or progression, as it is commonly found in a specific type of cancer.
Gene→Variant (gene-first): 3417:R132H
Genes: 3417
Variants: R132H
In metastatic breast cancer, HER2 activating mutations frequently co-occur with mutations in the PIK3CA, TP53, or E-cadherin genes. Of these co-occurring mutations, HER2 and PIK3CA mutations are the most prevalent gene p
[Paragraph-level] PMCID: PMC10527017 Section: ABSTRACT PassageIndex: 1
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the resistance of HP breast cancers to the pan-HER tyrosine kinase inhibitor, neratinib, and the effectiveness of combining neratinib with trastuzumab deruxtecan and CDK4/6 inhibitors, indicating a correlation with treatment response. Oncogenic: The study involves genetically engineered mice with the HER2V777L mutation, showing accelerated tumor formation and increased invasion, which supports the notion that this somatic variant contributes to tumor development and progression.
Gene→Variant (gene-first): 2064:V777L
Genes: 2064
Variants: V777L
ALK-break positive non-small cell lung cancer (NSCLC) patients initially respond to crizotinib, but resistance occurs inevitably. In this study we aimed to identify fusion genes in crizotinib resistant tumor samples. Re-
[Paragraph-level] PMCID: PMC4821611 Section: ABSTRACT PassageIndex: 1
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses ALK mutations (p.C1156Y and p.G1269A) in the context of crizotinib resistance, indicating a correlation between these variants and resistance to the therapy. Oncogenic: The ALK mutations are described as being detected in post-treatment tumor samples, suggesting their contribution to tumor development or progression in the context of crizotinib resistance.
Gene→Variant (gene-first): 238:p.C1156Y 238:p.G1269A
Genes: 238
Variants: p.C1156Y p.G1269A
Mutations in ALK, EGFR and KRAS have been reported to confer resistance against crizotinib. To determine presence of mutations in these genes in the three post-treatment samples, we inspected the RNA-seq bam files in IGV
[Paragraph-level] PMCID: PMC4821611 Section: RESULTS PassageIndex: 10
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses mutations in the ALK gene, specifically p.C1156Y and p.G1269A, which have been reported to confer resistance against crizotinib, indicating a correlation with treatment response. Oncogenic: The presence of mutations in the ALK gene, such as p.C1156Y and p.G1269A, suggests that these somatic variants contribute to tumor development or progression, as they were identified in post-treatment tumor samples.
Gene→Variant (gene-first): 238:c.3467G>A 238:c.3806G>C 238:p.C1156Y 238:p.G1269A
Genes: 238
Variants: c.3467G>A c.3806G>C p.C1156Y p.G1269A
In TERT-NHUC, abolishing PLCgamma1 phosphorylation significantly reduced the increase in saturation density associated with S249C FGFR3 (13% vs. 24%, p=0.05) (Figure 6a), suggesting that PLCgamma1 signaling contributes t
[Paragraph-level] PMCID: PMC2789045 Section: RESULTS PassageIndex: 23
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses how the S249C and K652E mutations affect cell viability and signaling pathways, indicating that these variants alter molecular or biochemical functions related to cell growth and density. Oncogenic: The evidence suggests that the S249C and K652E mutations contribute to tumor development or progression by affecting cell cycle phases and viability, which are indicative of cancer-driving behavior.
Gene→Variant (gene-first): 2261:K652E 2261:S249C 2261:Y762F
Genes: 2261
Variants: K652E S249C Y762F
To clarify whether the lack of constitutive PLCgamma1 phosphorylation may explain the different phenotypic behavior associated with the K652E mutation, we used a construct encoding a S249C FGFR3 protein with a mutated PL
[Paragraph-level] PMCID: PMC2789045 Section: RESULTS PassageIndex: 22
Evidence Type(s): Oncogenic, Functional
Justification: Oncogenic: The passage discusses the S249C+Y762F FGFR3 mutant protein's ability to induce morphological transformation and increased proliferation in NIH-3T3 cells, indicating its role in tumor development or progression. Functional: The passage describes how the S249C+Y762F mutation affects the phosphorylation of PLCgamma1 and alters the activation of downstream signaling pathways, demonstrating a change in molecular function.
Gene→Variant (gene-first): 2261:K652E 2261:S249C 2261:Y762F
Genes: 2261
Variants: K652E S249C Y762F
As expected, FGF1 induced phosphorylation of FRS2alpha, ERK1/2 and PLCgamma1 in normal urothelial cells over-expressing wildtype FGFR3 (Figure 4b). Consistent with their complete ligand-independence, FGF1 treatment faile
[Paragraph-level] PMCID: PMC2789045 Section: RESULTS PassageIndex: 20
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses how the K652E, S249C, and Y375C mutations alter the signaling response to FGF1 treatment, indicating that these variants affect molecular function related to phosphorylation and activation of signaling pathways. Oncogenic: The context of the mutations being discussed in relation to their effects on signaling pathways suggests that they may contribute to tumor development or progression, particularly given the focus on their responses in cancer-related cellular contexts.
Gene→Variant (gene-first): 2261:K652E 2261:S249C 2261:Y375C
Genes: 2261
Variants: K652E S249C Y375C
We next examined whether cells expressing wildtype and mutant FGFR3 were responsive to FGF1 stimulation in terms of receptor activation (Figure 4a, Supplementary Figure 5) and signaling (Figure 4b, Supplementary Figure 5
[Paragraph-level] PMCID: PMC2789045 Section: RESULTS PassageIndex: 19
Evidence Type(s): Predictive, Functional
Justification: Predictive: The passage discusses the response of cells expressing mutant FGFR3 variants (S249C, Y375C, K652E) to FGF1 stimulation, indicating a correlation with receptor activation and signaling, which relates to treatment response. Functional: The passage describes how the variants S249C, Y375C, and K652E affect the phosphorylation of FGFR3, indicating that these mutations alter the molecular function of the receptor in response to ligand stimulation.
Gene→Variant (gene-first): 2261:K652E 2261:S249C 2261:Y375C
Genes: 2261
Variants: K652E S249C Y375C
Signaling was examined in cells at various degrees of confluence, in full and depleted medium (Figure 3c, Supplementary Figure 4b). In all conditions tested, no differences were observed between mutant and control cells
[Paragraph-level] PMCID: PMC2789045 Section: RESULTS PassageIndex: 16
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses the increased phosphorylation of PLCgamma1 specifically in cells expressing the S249C and Y375C FGFR3 variants, indicating that these variants alter molecular function. Oncogenic: The mention of increased phosphorylation of signaling proteins in cells expressing the FGFR3 mutants suggests that these variants contribute to tumor development or progression.
Gene→Variant (gene-first): 2261:K652E 2261:S249C 2261:Y375C
Genes: 2261
Variants: K652E S249C Y375C
To investigate the reason for the differential behavior of cells expressing K652E FGFR3, we assessed the phosphorylation levels of FGFR3 mutant proteins and downstream effectors in urothelial cells. All mutant forms of F
[Paragraph-level] PMCID: PMC2789045 Section: RESULTS PassageIndex: 15
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses how the K652E, S249C, and Y375C variants of FGFR3 alter phosphorylation levels and dimerization behavior, indicating changes in molecular function. Oncogenic: The variants are described in the context of their constitutive activation and behavior in urothelial cells, suggesting their role in tumor development or progression.
Gene→Variant (gene-first): 2261:K652E 2261:S249C 2261:Y375C
Genes: 2261
Variants: K652E S249C Y375C
Three proteins involved in cell survival, MCL1, BCL-XL, and BCL2, were up-regulated in confluent cells expressing all types of mutant FGFR3 (Figure 2d, Supplementary Figure 3b). Surprisingly, there was no difference in t
[Paragraph-level] PMCID: PMC2789045 Section: RESULTS PassageIndex: 13
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses the expression of proteins involved in cell survival and suggests that the K652E variant may alter the viability of cells, indicating a change in molecular function. Oncogenic: The context implies that the K652E variant contributes to tumor behavior by affecting cell viability, which is a characteristic of oncogenic variants.
Gene→Variant (gene-first): 2261:K652E
Genes: 2261
Variants: K652E
Consistent with their altered cell cycle profile, confluent TERT-NHUC expressing mutant FGFR3 exhibited changes in cell cycle-related proteins (Figure 2d, Supplementary Figure 3a). Whilst in control cells the expression
[Paragraph-level] PMCID: PMC2789045 Section: RESULTS PassageIndex: 12
Evidence Type(s): Functional
Justification: Functional: The passage discusses how the variants S249C, Y375C, and K652E FGFR3 alter the expression and phosphorylation of cell cycle-related proteins, indicating a change in molecular function.
Gene→Variant (gene-first): 2261:K652E 2261:S249C 2261:Y375C
Genes: 2261
Variants: K652E S249C Y375C
Cells expressing S249C and Y375C FGFR3 were significantly more viable at confluence compared to controls or cells expressing wildtype FGFR3 (p<=0.001). On days 12 (Figure 2c) and 15 (data not shown), on average 45% of S2
[Paragraph-level] PMCID: PMC2789045 Section: RESULTS PassageIndex: 10
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses the viability of cells expressing specific variants (S249C and Y375C) compared to controls, indicating that these variants alter the molecular or biochemical function of FGFR3, affecting cell viability. Oncogenic: The evidence suggests that the variants S249C and Y375C contribute to tumor development or progression by enhancing cell viability, which is a characteristic of oncogenic behavior.
Gene→Variant (gene-first): 2261:K652E 2261:S249C 2261:Y375C
Genes: 2261
Variants: K652E S249C Y375C
In controls, the number of cells in the G0/G1 phase of the cell cycle progressively increased at confluence, while the number of viable cells decreased. No significant differences in cell cycle profile or viability were
[Paragraph-level] PMCID: PMC2789045 Section: RESULTS PassageIndex: 9
Evidence Type(s): Functional
Justification: Functional: The mention of K652E and Y375C variants also suggests alterations in cell cycle profiles, indicating a change in molecular function related to cell cycle dynamics.
Gene→Variant (gene-first): 2261:K652E 2261:S249C 2261:Y375C
Genes: 2261
Variants: K652E S249C Y375C
The saturation density of cells expressing K652E FGFR3 was similar to controls and cells expressing wildtype FGFR3 or S249C KD. Therefore, the magnitude of the phenotypic effect was of the order S249C>Y375C>K652E=Wildtyp
[Paragraph-level] PMCID: PMC2789045 Section: RESULTS PassageIndex: 6
Evidence Type(s): Diagnostic, Functional
Justification: Diagnostic: The passage discusses the relative frequencies of the mutations K652E, S249C, and Y375C in bladder tumors, indicating an association with the disease. Functional: The passage mentions the phenotypic effects of the variants, suggesting that they alter the behavior of cells expressing these mutations compared to controls.
Gene→Variant (gene-first): 2261:K652E 2261:S249C 2261:Y375C
Genes: 2261
Variants: K652E S249C Y375C
Next we studied the effects of mutant FGFR3 in normal urothelial cells by expressing S249C, Y375C and K652E FGFR3 in TERT-NHUC. Expression levels were comparable to those observed in the bladder cancer cell line TCC97-7,
[Paragraph-level] PMCID: PMC2789045 Section: RESULTS PassageIndex: 5
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses how the expression of mutant FGFR3 variants S249C and Y375C alters the saturation density and morphology of normal urothelial cells, indicating a change in molecular or biochemical function. Oncogenic: The expression of the mutant FGFR3 variants is associated with changes in cell behavior, such as increased saturation density and altered morphology, which suggests a contribution to tumor development or progression.
Gene→Variant (gene-first): 2261:K652E 2261:S249C 2261:Y375C
Genes: 2261
Variants: K652E S249C Y375C
Initially, we assessed the ability of three mutant forms of FGFR3 that are found in UC (S249C, Y375C, and K652E) to transform NIH-3T3 cells. In these cells, expression of all FGFR3 mutations resulted in a transformed spi
[Paragraph-level] PMCID: PMC2789045 Section: RESULTS PassageIndex: 3
Evidence Type(s): Oncogenic, Functional
Justification: Oncogenic: The passage discusses the ability of the FGFR3 mutations (S249C, Y375C, and K652E) to transform NIH-3T3 cells, indicating that these somatic variants contribute to tumor development or progression. Functional: The passage describes how the FGFR3 mutations alter molecular function, specifically through increased phosphorylation of various proteins and changes in cell morphology and proliferation, demonstrating their biochemical activity.
Gene→Variant (gene-first): 2261:K652E 2261:S249C 2261:Y375C
Genes: 2261
Variants: K652E S249C Y375C
The 14 NF1-associated gliomas belonging to the molecular high-grade group did not form a distinct epigenomic cluster but instead aligned with other sporadic reference entities, most frequently high-grade astrocytoma with
[Paragraph-level] PMCID: PMC9468105 Section: RESULTS PassageIndex: 14
Evidence Type(s): Diagnostic, Prognostic
Justification: Diagnostic: The passage discusses the association of the BRAF p.V600E mutation with pleomorphic xanthoastrocytoma, indicating its role in defining or classifying this specific tumor type. Prognostic: The Kaplan-Meier survival analysis mentioned in the passage indicates that patients with NF1-associated gliomas have inferior outcomes, suggesting a correlation between the presence of certain mutations and disease prognosis.
Gene→Variant (gene-first): 673:p.V600E
Genes: 673
Variants: p.V600E
Consistent with an autosomal dominant tumor predisposition syndrome, these gliomas arising in the setting of NF1 developed in patients with a heterozygous germline mutation or deletion involving one of two NF1 alleles (a
[Paragraph-level] PMCID: PMC9468105 Section: RESULTS PassageIndex: 4
Evidence Type(s): Predisposing, Oncogenic
Justification: Predisposing: The passage describes a germline mutation (p.R1276*) associated with an autosomal dominant tumor predisposition syndrome, indicating inherited risk for developing gliomas. Oncogenic: The passage discusses the somatic inactivation of the remaining wild-type NF1 allele, which contributes to tumor development in gliomas, indicating that the variant plays a role in oncogenesis.
Gene→Variant (gene-first): 4763:c.4110 + 2 T > G 4763:p.R1276*
Genes: 4763
Variants: c.4110 + 2 T > G p.R1276*
Colorectal cancer (CRC) manifests after the accumulation of genetic and epigenetic alterations along with tumor microenvironments. MicroRNA (miRNA/miR) molecules have been revealed to serve in critical roles in the progr
[Paragraph-level] PMCID: PMC7068240 Section: ABSTRACT PassageIndex: 1
Evidence Type(s): Prognostic, Diagnostic
Justification: Prognostic: The passage discusses the association of high miR-31 expression with poorer mortality and shorter median survival time in patients with advanced colorectal cancer, indicating a prognostic relationship. Diagnostic: The study evaluates the potential of miRNAs as biomarkers for colorectal cancer, suggesting that the presence of the BRAF V600E mutation can be used to classify tumors based on miR-31 expression levels.
Gene→Variant (gene-first): 673:V600E 673:serine/threonine
Genes: 673
Variants: V600E serine/threonine
SF3B1 mutation is considered a founder clone, however we observed 2 patients in which the mutation arose during disease evolution. The first patient was a 74-year-old man who was diagnosed with MDS-EB with trisomy 8 and
[Paragraph-level] PMCID: PMC10015977 Section: RESULTS PassageIndex: 24
Evidence Type(s): Oncogenic, Functional
Justification: Oncogenic: The passage discusses the acquisition of the SF3B1 R625C, K700E, and SETBP1 E862K mutations during disease evolution, indicating their role in tumor development and progression in the context of MDS-EB transforming to AML. Functional: The mention of the SF3B1 mutations leading to changes in bone marrow morphology, such as the appearance of ring sideroblasts, suggests that these variants alter molecular or biochemical function related to the disease.
Gene→Variant (gene-first): 26040:E862K 23451:K700E 23451:R625C
Genes: 26040 23451
Variants: E862K K700E R625C
Within the entire MDS cohort, by univariate analysis (Supplementary Table 2), the following parameters were associated with worse outcomes: higher BM blasts percentage; lower hemoglobin, platelet and MCV; prior history o
[Paragraph-level] PMCID: PMC10015977 Section: RESULTS PassageIndex: 21
Evidence Type(s): Prognostic
Justification: Prognostic: The passage discusses the absence of the SF3B1 K700E mutation as an independent predictor of worse overall survival (OS), indicating a correlation between the variant and disease outcome.
Gene→Variant (gene-first): 23451:K700E
Genes: 23451
Variants: K700E
As a next step, among low-grade MDS (<5% BM blasts and <1% PB blasts) with therapy-related cases excluded, we explored to see if the differences persisted between K700E and non-K700E SF3B1mut MDS groups even after applyi
[Paragraph-level] PMCID: PMC10015977 Section: RESULTS PassageIndex: 20
Evidence Type(s): Prognostic, Diagnostic
Justification: Prognostic: The passage indicates that K700E SF3B1mut MDS showed a trend for longer overall survival (OS) compared to non-K700E SF3B1mut MDS, suggesting a correlation with disease outcome independent of therapy. Diagnostic: The passage discusses the classification of K700E SF3B1mut MDS in relation to the proposed 2020 IWG-PM criteria, indicating its use in defining or classifying a disease subtype.
Gene→Variant (gene-first): 23451:K700E
Genes: 23451
Variants: K700E
Therapy-related MDS cases were distributed equally between K700E and non-K700E groups. Within low-grade MDS (MDS-SLD, MDS-MLD and MDS-RS), we excluded therapy-related MDS cases due to a relatively higher representation o
[Paragraph-level] PMCID: PMC10015977 Section: RESULTS PassageIndex: 19
Evidence Type(s): Prognostic, Diagnostic
Justification: Prognostic: The passage indicates that K700E SF3B1mut MDS is associated with significantly better overall survival (OS) compared to SF3B1wt MDS, suggesting a correlation with disease outcome independent of therapy. Diagnostic: The mention of K700E in the context of classifying MDS subtypes (e.g., comparing K700E SF3B1mut MDS to non-K700E SF3B1mut MDS) supports its role in defining or classifying a disease or subtype.
Gene→Variant (gene-first): 23451:K700E
Genes: 23451
Variants: K700E
Between K700E vs. non-K700E SF3B1mut MDS categories, 9 of 39 (23%) K700E SF3B1mut MDS patients died compared to 4 of 55 (7%; p=0.02) non-K700E patients; findings were similar in low-grade MDS patients (16% vs. 3%, p=0.04
[Paragraph-level] PMCID: PMC10015977 Section: RESULTS PassageIndex: 18
Evidence Type(s): Prognostic, Diagnostic
Justification: Prognostic: The passage discusses the overall survival (OS) rates of K700E SF3B1mut MDS patients compared to non-K700E patients, indicating a correlation with disease outcome independent of therapy. Diagnostic: The mention of K700E SF3B1mut MDS patients in relation to non-K700E patients suggests a classification or association with a specific disease subtype.
Gene→Variant (gene-first): 23451:K700E
Genes: 23451
Variants: K700E
Within the MDS-EB categories, compared to SF3B1wt, there were no significant differences in OS of K700E SF3B1mut (median OS, not reached vs. 17 7 month, p=0 355) and non-K700E SF3B1mut (median OS, 20 5 vs. 17 7 months; p
[Paragraph-level] PMCID: PMC10015977 Section: RESULTS PassageIndex: 17
Evidence Type(s): Prognostic
Justification: Prognostic: The passage discusses overall survival (OS) in relation to the K700E variant, indicating that it correlates with disease outcome independent of therapy.
Gene→Variant (gene-first): 23451:K700E
Genes: 23451
Variants: K700E
The majority of patients in all 3 categories were treated with an HMA: 16/17 (94%) K700E mutated patients; 16/19 (84%) non-K700E mutated patients; and 217/277 (78%) SF3B1wt patients. The treatment details are provided in
[Paragraph-level] PMCID: PMC10015977 Section: RESULTS PassageIndex: 16
Evidence Type(s): Prognostic, Diagnostic
Justification: Prognostic: The passage discusses the overall survival (OS) outcomes of K700E SF3B1mut MDS patients compared to SF3B1wt patients, indicating that the K700E variant correlates with better disease outcomes independent of therapy. Diagnostic: The K700E variant is used to classify and differentiate between SF3B1mut and SF3B1wt MDS patients, indicating its role in defining disease subtypes.
Gene→Variant (gene-first): 23451:K700E
Genes: 23451
Variants: K700E
Using rMATS, we identified the five most frequent types of alternative splicing events (alternative 5' splice site, A5SS; alternative 3' splice site, A3SS; mutually exclusive exon, MXE; retained intron, RI and skipped ex
[Paragraph-level] PMCID: PMC10015977 Section: RESULTS PassageIndex: 14
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses the impact of the SF3B1 K700E variant on alternative splicing events, indicating that it alters molecular function related to splicing and gene expression. Oncogenic: The SF3B1 K700E variant is associated with mutated myelodysplastic syndromes (MDS), suggesting its role in tumor development or progression.
Gene→Variant (gene-first): 23451:K700E
Genes: 23451
Variants: K700E
Splicing analysis between K700E and non-K700E mutated MDS
[Paragraph-level] PMCID: PMC10015977 Section: RESULTS PassageIndex: 13
Evidence Type(s): Functional
Justification: Functional: The passage discusses splicing analysis related to the K700E variant, indicating an alteration in molecular function.
Gene→Variant (gene-first): 23451:K700E
Genes: 23451
Variants: K700E
There were no significant differences in normal vs. complex karyotype. When cytogenetic aberrations were classified using the comprehensive cytogenetic scoring system (CCSS; scores from 0-5), SF3B1mut K700E mutated patie
[Paragraph-level] PMCID: PMC10015977 Section: RESULTS PassageIndex: 12
Evidence Type(s): Diagnostic, Oncogenic
Justification: Diagnostic: The passage discusses the classification of patients based on the presence of the K700E variant, indicating its association with lower CCSS scores, which suggests a role in defining or classifying a disease subtype. Oncogenic: The mention of the K700E variant in the context of patients with MDS (myelodysplastic syndromes) implies its contribution to tumor development or progression, as it is associated with specific cytogenetic aberrations.
Gene→Variant (gene-first): 23451:K700E
Genes: 23451
Variants: K700E
There was no difference in the median SF3B1 variant allele frequency (VAF) between the 2 groups. The frequency of RUNX1 mutation was significantly higher in non-K700E cases (26% vs. 7 3%, p=0 012), and mutations in BCOR
[Paragraph-level] PMCID: PMC10015977 Section: RESULTS PassageIndex: 11
Evidence Type(s): None
Justification: Not enough information in this passage.
Gene→Variant (gene-first): 23451:K700E
Genes: 23451
Variants: K700E
We compared the clinico-pathologic features of 55 K700E vs. 39 non-K700E treatment naive SF3B1mut MDS patients (Table 2). MDS with SF3B1 K700E mutations had a higher percentage of ring sideroblasts (median 50% vs. 34%; p
[Paragraph-level] PMCID: PMC10015977 Section: RESULTS PassageIndex: 10
Evidence Type(s): Diagnostic, Oncogenic
Justification: Diagnostic: The passage discusses the clinico-pathologic features of MDS patients with K700E mutations, indicating that these mutations are associated with specific disease characteristics and classifications, such as higher percentages of ring sideroblasts and differences in IPSS-R categories. Oncogenic: The K700E mutation in SF3B1 is implicated in the classification of MDS patients and is associated with specific tumor characteristics, suggesting its role in tumor development or progression.
Gene→Variant (gene-first): 23451:K700E
Genes: 23451
Variants: K700E
Comparison between SF3B1 K700E and non-K700E mutated MDS
[Paragraph-level] PMCID: PMC10015977 Section: RESULTS PassageIndex: 9
Evidence Type(s): None
Justification: Not enough information in this passage.
Gene→Variant (gene-first): 23451:K700E
Genes: 23451
Variants: K700E
BM aspirates from all patients underwent NGS analysis with an 81-gene panel at the time of diagnosis. The most frequent SF3B1 mutation, noted in ~60% of all patients, was the hotspot K700E. Among the remaining mutations
[Paragraph-level] PMCID: PMC10015977 Section: RESULTS PassageIndex: 8
Evidence Type(s): Diagnostic, Oncogenic
Justification: Diagnostic: The passage discusses the frequency of specific mutations, including K666, K700E, and R625, in patients with MDS, indicating their association with the disease and their role in defining the mutational landscape. Oncogenic: The mention of SF3B1 mutations, including K700E, K666, and R625, as frequent mutations in patients with MDS suggests that these somatic variants contribute to tumor development or progression in this context.
Gene→Variant (gene-first): 23451:K666 23451:K700E 23451:R625
Genes: 23451
Variants: K666 K700E R625
Mutational landscape of SF3B1mut MDS (K700E and non-K700E subtypes)
[Paragraph-level] PMCID: PMC10015977 Section: RESULTS PassageIndex: 7
Evidence Type(s): Diagnostic, Oncogenic
Justification: Diagnostic: The passage discusses the mutational landscape of SF3B1 mutations, specifically mentioning the K700E subtype, which indicates its role in classifying or defining a disease subtype. Oncogenic: The mention of K700E in the context of SF3B1 mutations suggests its contribution to tumor development or progression, as it is associated with a specific subtype of myelodysplastic syndromes (MDS).
Gene→Variant (gene-first): 23451:K700E
Genes: 23451
Variants: K700E
Myelodysplastic syndromes with SF3B1 mutations are regarded to have a favorable prognosis by both WHO and the International Working Group for Prognostication of MDS (IWG-PM). However, in this article, we show that only M
[Paragraph-level] PMCID: PMC10015977 Section: ABSTRACT PassageIndex: 12
Evidence Type(s): Diagnostic, Prognostic
Justification: Diagnostic: The passage discusses how MDS with SF3B1 K700E mutations can be used to refine sub-classification and risk assessment criteria, indicating its role in defining or classifying a disease subtype. Prognostic: The passage states that MDS with SF3B1 K700E mutations is regarded to have a favorable prognosis, which correlates with disease outcome independent of therapy.
Gene→Variant (gene-first): 23451:K700E
Genes: 23451
Variants: K700E
Myelodysplastic syndromes (MDS) with K700E and non-K700E SF3B1 mutations show distinct clinicopathological and genomic characteristics, with only SF3B1 K700E mutated MDS showing a significantly better OS compared to non-
[Paragraph-level] PMCID: PMC10015977 Section: ABSTRACT PassageIndex: 10
Evidence Type(s): Prognostic, Diagnostic
Justification: Prognostic: The passage indicates that SF3B1 K700E mutated MDS shows significantly better overall survival (OS) compared to non-K700E mutations, suggesting a correlation with disease outcome. Diagnostic: The mention of distinct clinicopathological and genomic characteristics associated with K700E and non-K700E SF3B1 mutations implies that the mutation type is used for risk-assessment and classification of MDS.
Gene→Variant (gene-first): 23451:K700E
Genes: 23451
Variants: K700E
Fifty-five (60%) patients carried K700E. Recurrent non-K700E mutations (39, 40%) included R625, H662 and K666. Compared to SF3B1mut-K700E, non-K700E patients had a lower median ANC (1 8 vs. 2 4, p=0 005) and were frequen
[Paragraph-level] PMCID: PMC10015977 Section: ABSTRACT PassageIndex: 6
Evidence Type(s): Diagnostic, Prognostic, Oncogenic
Justification: Diagnostic: The passage discusses the association of K700E and non-K700E mutations with specific patient characteristics and outcomes, indicating their role in classifying patients with MDS. Prognostic: The passage reports on overall survival outcomes associated with SF3B1 mutations, including K700E, indicating that these variants correlate with disease prognosis independent of therapy. Oncogenic: The mention of mutations such as K700E contributing to the classification of MDS and their association with specific patient outcomes suggests a role in tumor development or progression.
Gene→Variant (gene-first): 23451:K666 23451:K700 23451:K700E 23451:R625
Genes: 23451
Variants: K666 K700 K700E R625
We analyzed the clinical-pathologic features and outcomes of a single-institutional series of 94 (19%) SF3B1mut and 415 SF3B1wt treatment-naive MDS patients and explored the differences between K700E and non-K700E.
[Paragraph-level] PMCID: PMC10015977 Section: ABSTRACT PassageIndex: 4
Evidence Type(s): Diagnostic, Oncogenic
Justification: Diagnostic: The passage discusses the analysis of clinical-pathologic features and outcomes in MDS patients, specifically exploring differences between K700E and non-K700E variants, indicating a potential role in classification or association with disease characteristics. Oncogenic: The mention of analyzing the clinical-pathologic features of SF3B1mut patients, including K700E, suggests that this variant may contribute to tumor development or progression in the context of MDS.
Gene→Variant (gene-first): 23451:K700E
Genes: 23451
Variants: K700E
SF3B1 mutations (SF3B1mut) in myelodysplastic syndromes (MDS) frequently involve codon K700E and have a favorable prognosis. The prognostic effect of non-K700E SF3B1mut is uncertain.
[Paragraph-level] PMCID: PMC10015977 Section: ABSTRACT PassageIndex: 2
Evidence Type(s): Prognostic, Diagnostic
Justification: Prognostic: The passage states that SF3B1 mutations, including K700E, have a favorable prognosis in myelodysplastic syndromes, indicating a correlation with disease outcome. Diagnostic: The mention of SF3B1 mutations in the context of myelodysplastic syndromes suggests that these mutations, including K700E, are used to classify or define the disease.
Gene→Variant (gene-first): 23451:K700E
Genes: 23451
Variants: K700E
PTEN expression loss was found in 18 patients (31.6%, Figure 2a). Thirty-nine patients were positive for PTEN expression, in which 17 (29.8%), 14 (24.6%), and 8 (14%) specimens were weak positive, positive and strong pos
[Paragraph-level] PMCID: PMC3141770 Section: RESULTS PassageIndex: 6
Evidence Type(s): Oncogenic
Justification: Oncogenic: The passage indicates that the H1047R mutation is associated with PTEN loss in patients, suggesting that it contributes to tumor development or progression.
Gene→Variant (gene-first): 5290:H1047R
Genes: 5290
Variants: H1047R
The overall incidence of PIK3CA mutations was 12.3% (7 in 57 samples). The majority of mutations occurred at two hotspots, H1047R (7%, 4 samples) at exon 20 encoding the kinase domain (Figure 1a), and E542K (1.8%, 1 samp
[Paragraph-level] PMCID: PMC3141770 Section: RESULTS PassageIndex: 5
Evidence Type(s): Diagnostic, Oncogenic
Justification: Diagnostic: The passage discusses the incidence of PIK3CA mutations and their occurrence in specific samples, indicating their association with the disease. Oncogenic: The mention of PIK3CA mutations, including E542K and H1047R, suggests their role in tumor development, as they are described as mutations found in tumor samples.
Gene→Variant (gene-first): 5290:E542K 5290:H1047R 5728:T1052A
Genes: 5290 5728
Variants: E542K H1047R T1052A
OS of EGFR-TKI treated patients was similar for 1st and 2nd-line EGFR-TKI treatment. Patients not treated with EGFR-TKI had no benefit in OS. Re-biopsies obtained at progression revealed an EGFR-T790M mutation in 73% (n=
[Paragraph-level] PMCID: PMC5652823 Section: ABSTRACT PassageIndex: 7
Evidence Type(s): Predictive, Diagnostic
Justification: Predictive: The passage indicates that patients with the EGFR-T790M mutation responded to the 3rd-generation EGFR-TKI osimertinib, suggesting a correlation between the variant and treatment response. Diagnostic: The EGFR-T790M mutation is mentioned as being revealed in re-biopsies at progression, indicating its role in defining or confirming the presence of a specific disease state in patients treated with EGFR-TKIs.
Gene→Variant (gene-first): 1956:T790M
Genes: 1956
Variants: T790M
BACKGROUND: The BRAF inhibitors vemurafenib and dabrafenib are currently the standard treatment for metastatic melanoma with BRAF V600 mutations. However, given the rarity of noncutaneous melanoma, including acral and mu
[Paragraph-level] PMCID: PMC5122709 Section: ABSTRACT PassageIndex: 1
Evidence Type(s): Predictive, Diagnostic
Justification: Predictive: The passage discusses the effectiveness of BRAF inhibitors in patients with metastatic melanoma harboring BRAF V600 mutations, indicating a correlation with treatment response. Diagnostic: The BRAF V600 mutation is used to define and classify patients with metastatic melanoma, as all patients in the study had BRAFV600E mutations.
Gene→Variant (gene-first): 673:V600
Genes: 673
Variants: V600
Mutations previously correlated with response were detected in five tumours, four with exon 19 deletions and one with an exon 21 missense L858R point mutation. Increased gene copy number was observed in thirteen tumours,
[Paragraph-level] PMCID: PMC1952070 Section: ABSTRACT PassageIndex: 6
Evidence Type(s): Predictive, Diagnostic
Justification: Predictive: The passage discusses mutations, including the L858R point mutation, in the context of their correlation with response to treatment, indicating a predictive relationship. Diagnostic: The mention of the L858R mutation as part of a group of mutations previously correlated with response suggests its role in defining or classifying a disease subtype.
Gene→Variant (gene-first): 1956:L858R
Genes: 1956
Variants: L858R
PIK3CA encodes the p110alpha catalytic subunit of the phosphoinositide-3-kinase heterodimer. Upon activation, PI3K phosphorylates phosphatidylinositol-4,5-bisphosphate (PIP2) at the third position, generating PIP3. PIP3
[Paragraph-level] PMCID: PMC3542862 Section: RESULTS PassageIndex: 7
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses how mutations at amino acids p.Glu542 and p.His1047 increase intracellular AKT phosphorylation, indicating an alteration in molecular function related to AKT activation. Oncogenic: The mention of increased AKT phosphorylation due to the H1047R mutation suggests that this somatic variant contributes to tumor development or progression by promoting cellular processes such as survival and proliferation.
Gene→Variant (gene-first): 5290:H1047R 5290:p.Glu542 5290:p.His1047
Genes: 5290
Variants: H1047R p.Glu542 p.His1047
To provide additional evidence for pathogenic PI3K somatic mutations in macrodactyly, exons 2, 10 and 21 were amplified from DNA extracted from the affected tissue of seven additional unrelated macrodactyly patients as w
[Paragraph-level] PMCID: PMC3542862 Section: RESULTS PassageIndex: 6
Evidence Type(s): Oncogenic, Functional
Justification: Oncogenic: The passage discusses somatic mutations in the PIK3CA gene, specifically mentioning that the E542K, H1047R, and H1047L mutations are known gain-of-function mutations frequently mutated in cancer, indicating their contribution to tumor development or progression. Functional: The passage notes that the mutations E542K and H1047 (both H1047R and H1047L) are located in the helical and kinase domains of the PI3K protein, which are known hotspots for somatic gain-of-function mutations, suggesting that these variants alter the molecular function of the protein.
Gene→Variant (gene-first): 5290:E542K 5290:H1047L 5290:H1047R 5163:R115P 5290:p.Glu542 5290:p.His1047
Genes: 5290 5163
Variants: E542K H1047L H1047R R115P p.Glu542 p.His1047
Additional evidence suggested that the R115P mutation in PIK3CA (PI3K) was a likely candidate for macrodactyly. First, somatic activation of AKT, a downstream target of PI3K, was recently described in patients with Prote
[Paragraph-level] PMCID: PMC3542862 Section: RESULTS PassageIndex: 5
Evidence Type(s): Diagnostic, Oncogenic
Justification: Diagnostic: The R115P mutation in PIK3CA is suggested as a likely candidate for macrodactyly, indicating its association with a specific disease. Oncogenic: The R115L mutation is annotated in a database of somatic mutations in cancer, suggesting its contribution to tumor development or progression.
Gene→Variant (gene-first): 5290:R115L 5163:R115P 5290:p.Arg115
Genes: 5290 5163
Variants: R115L R115P p.Arg115
NS sequence variants were excluded as disease candidates by their (a) presence in 28 control samples sequenced by our group using a similar method, (b) presence in the exome sequence of the germline sample and (c) presen
[Paragraph-level] PMCID: PMC3542862 Section: RESULTS PassageIndex: 4
Evidence Type(s): Diagnostic, Oncogenic
Justification: Diagnostic: The passage discusses the presence of the R115P mutation in PIK3CA in lesional tissue but not in blood, indicating its potential role in defining or confirming a disease state. Oncogenic: The R115P mutation in PIK3CA is described as potentially deleterious and is present in lesional tissue, suggesting it contributes to tumor development or progression.
Gene→Variant (gene-first): 91544:C392G 5163:R115P
Genes: 91544 5163
Variants: C392G R115P
Four additional K-Ras mutations (Leu19Phe (1 out of 106 tumours), Lys117Asn (1 out of 106), Ala146Thr (7 out of 106) and Arg164Gln (1 out of 106)) were identified. Lys117Asn and Ala146Thr had phenotypes similar to the ho
[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
We investigated whether the above large-scale patterns characterize all KRAS, HRAS and NRAS hotspot variants, by projecting the amino acid substitutions at G12, G13 and Q61 and observed an overall similar pattern, but wi
[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
To visualize the relative changes in GAP-mediated hydrolysis and RAF affinity across all 935 RAS family variants, we extended PHATE to 2D and followed a similar procedure as above. 2D PHATE for GAP-mediated hydrolysis (F
[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
Additionally, we predicted relative RAF affinity changes for amino acid substitutions lacking experimental measurements (15 out of 23; Fig. 4B). These include G12S, which we predict has a decreased RAF affinity like othe
[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
We investigated how the 23 KRAS variants change RAF affinity by first identifying the computational scores exhibiting strongest associations with this property (Fig. 4), all of which were from 3D structure and emphasize
[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
In our second approach, we used PHATE dimensionality reduction to score overall similarities among the 935 variants from 7 RAS genes. We performed 1D PHATE (PHATE1) analysis of the 5 computational scores that correlated
[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
In our first approach, we examined patterns among five computational scores (one protein sequence and four 3D structure-based scores) that correlate with the GAP-mediated hydrolysis rate (Fig. 3A and B). All four structu
[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
Because genetic variation outside of classic somatic hotspots has received relatively little attention, we next sought to quantify similarities among them by combining information across different experimental measuremen
[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
We developed a harmonized dataset for rapidly assessing mutational effects on the biochemical properties of the GTPase encoded by KRAS. We collected, processed, and categorized data derived from studying 23 KRAS hotspot
[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
Stratification analysis was also performed to evaluate the potential effects of TYMS rs3786362 in mCRC patients in the dominant model. Overall, the carriers of the risk G allele reduced PFS with respect to female, younge
[Paragraph-level] PMCID: PMC7545690 Section: RESULTS PassageIndex: 15
Evidence Type(s): Prognostic, Predictive
Justification: Prognostic: The passage discusses how the rs3786362 variant correlates with progression-free survival (PFS) and overall survival (OS) in metastatic colorectal cancer (mCRC) patients, indicating its association with disease outcomes independent of therapy. Predictive: The passage suggests that TYMS rs3786362 could be a predictive biomarker for survival in mCRC patients, indicating a potential correlation with treatment response in specific subgroups.
Gene→Variant (gene-first): 7298:rs3786362
Genes: 7298
Variants: rs3786362
Stratification analysis of rs3786362 in TYMS and mCRC survival
[Paragraph-level] PMCID: PMC7545690 Section: RESULTS PassageIndex: 14
Evidence Type(s): Prognostic
Justification: Prognostic: The passage indicates that rs3786362 is involved in stratification analysis related to mCRC survival, suggesting a correlation with disease outcome.
Gene→Variant (gene-first): 7298:rs3786362
Genes: 7298
Variants: rs3786362
In order to explore the correlation of rs3786362 in TYMS and responses to first-line chemotherapy in mCRC patients, we conducted three models including additive model, dominant model and recessive model for correlation a
[Paragraph-level] PMCID: PMC7545690 Section: RESULTS PassageIndex: 13
Evidence Type(s): Predictive
Justification: Predictive: The passage discusses the correlation of the variant rs3786362 with responses to first-line chemotherapy in mCRC patients, indicating that the G allele is associated with reduced disease control rate (DCR), which relates to treatment response.
Gene→Variant (gene-first): 7298:rs3786362
Genes: 7298
Variants: rs3786362
The correlation between rs3786362 in TYMS and DCR of mCRC patients
[Paragraph-level] PMCID: PMC7545690 Section: RESULTS PassageIndex: 12
Evidence Type(s): Predictive
Justification: Predictive: The passage discusses the correlation between the variant rs3786362 and the disease control rate (DCR) in metastatic colorectal cancer (mCRC) patients, indicating a relationship with treatment response.
Gene→Variant (gene-first): 7298:rs3786362
Genes: 7298
Variants: rs3786362
Kaplan-Meier curves of PFS and OS for TYMS rs3786362 in mCRC patients were depicted choosing the dominant model. Patients with AG/GG genotypes exhibited reduced PFS and OS compared with AA genotype (Figure 2).
[Paragraph-level] PMCID: PMC7545690 Section: RESULTS PassageIndex: 11
Evidence Type(s): Prognostic, Diagnostic
Justification: Prognostic: The passage discusses the correlation of the rs3786362 variant with progression-free survival (PFS) and overall survival (OS) in mCRC patients, indicating its association with disease outcome independent of therapy. Diagnostic: The variant rs3786362 is used to classify patients based on their genotypes (AG/GG vs. AA), which suggests its role in defining or associating with a disease subtype in mCRC.
Gene→Variant (gene-first): 7298:rs3786362
Genes: 7298
Variants: rs3786362
Owing to the positive findings of TYMS rs3786362 on PFS in our previous study, the correlation analysis of the selected SNP with OS was further conducted. Interestingly, TYMS rs3786362 was also associated with reduced OS
[Paragraph-level] PMCID: PMC7545690 Section: RESULTS PassageIndex: 10
Evidence Type(s): Prognostic, Diagnostic
Justification: Prognostic: The passage discusses the association of the variant rs3786362 with reduced overall survival (OS) and progression-free survival (PFS), indicating its correlation with disease outcomes independent of therapy. Diagnostic: The variant rs3786362 is associated with different genotypes (AG and AA) that correlate with reduced PFS and OS, suggesting its role in classifying disease outcomes based on genotype.
Gene→Variant (gene-first): 7298:rs3786362
Genes: 7298
Variants: rs3786362
The correlation between rs3786362 in TYMS and mCRC survival
[Paragraph-level] PMCID: PMC7545690 Section: RESULTS PassageIndex: 9
Evidence Type(s): Prognostic
Justification: Prognostic: The passage discusses the correlation between the variant rs3786362 and mCRC survival, indicating its association with disease outcome independent of therapy.
Gene→Variant (gene-first): 7298:rs3786362
Genes: 7298
Variants: rs3786362
We analyzed the association between 35 SNPs and PFS of mCRC patients in the additive model after genotyping (Supplementary Table S4). As shown in Table 1, we found that four SNPs (rs369803 in FOLH1, rs10432965 in FTCD, r
[Paragraph-level] PMCID: PMC7545690 Section: RESULTS PassageIndex: 8
Evidence Type(s): Prognostic, Predictive
Justification: Prognostic: The passage discusses the correlation of SNPs, specifically rs3786362 and rs369803, with progression-free survival (PFS) in metastatic colorectal cancer (mCRC) patients, indicating their association with disease outcome. Predictive: The passage mentions the correlation of SNPs with disease control rate (DCR), suggesting that these variants may influence treatment response in mCRC patients.
Gene→Variant (gene-first): 10841:rs10432965 2346:rs369803 7298:rs3786362 113235:rs4795436
Genes: 10841 2346 7298 113235
Variants: rs10432965 rs369803 rs3786362 rs4795436
The maximum tolerated dose was established as 40 mg/d; dose-limiting toxicities included reversible thrombocytopenia and nonhematologic toxicity. Across the entire study, the most common grade >= 3 treatment-emergent adv
[Paragraph-level] PMCID: PMC7325368 Section: ABSTRACT PassageIndex: 6
Evidence Type(s): Predictive, Diagnostic
Justification: Predictive: The passage discusses the response of patients with B-RAFV600E mutations to therapy, indicating a correlation between the variant and treatment outcomes in various cancers. Diagnostic: The mention of B-RAFV600E in the context of specific cancer types suggests its use as a biomarker to classify or define these diseases.
Gene→Variant (gene-first): 673:B-RAFV600E
Genes: 673
Variants: B-RAFV600E
Lifirafenib is an investigational, reversible inhibitor of B-RAFV600E, wild-type A-RAF, B-RAF, C-RAF, and EGFR. This first-in-human, phase I, dose-escalation/dose-expansion study evaluated the safety, tolerability, and e
[Paragraph-level] PMCID: PMC7325368 Section: ABSTRACT PassageIndex: 2
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses lifirafenib as an inhibitor specifically targeting B-RAFV600E, indicating a correlation with response to therapy in patients with B-RAF-mutated tumors. Oncogenic: The mention of B-RAFV600E in the context of mutated solid tumors suggests that this somatic variant contributes to tumor development or progression.
Gene→Variant (gene-first): 673:B-RAFV600E
Genes: 673
Variants: B-RAFV600E
Across the entire study, 2 patients with K-RAS mutations (endometrial cancer [20 mg/d] and codon 12-mutated NSCLC [30 mg/d], n = 1 each) had confirmed responses, which resulted in an ORR of 3.4%; 32 patients (54.2%) with
[Paragraph-level] PMCID: PMC7325368 Section: RESULTS PassageIndex: 11
Evidence Type(s): Predictive, Diagnostic, Oncogenic
Justification: Predictive: The passage discusses the confirmed responses and stable disease (SD) in patients with K-RAS mutations, including G13D, indicating a correlation with treatment response. Diagnostic: The mention of K-RAS mutations, including G13D, in the context of specific cancer types (endometrial cancer and NSCLC) suggests its role in classifying or defining these diseases. Oncogenic: The reference to K-RAS mutations, including G13D, contributing to tumor development in specific cancer types supports the classification of this variant as oncogenic.
Gene→Variant (gene-first): 3845:G13D
Genes: 3845
Variants: G13D
Patients with B-RAF and K-RAS mutations from both phases had responses (Table 3). Among patients with B-RAF mutations, 8 (15.1%) of 53 achieved PR, including 1 patient with melanoma who received prior RAF inhibitor thera
[Paragraph-level] PMCID: PMC7325368 Section: RESULTS PassageIndex: 10
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the responses of patients with B-RAF mutations to therapy, indicating a correlation between the B-RAFV600E variant and treatment response, which is characteristic of predictive evidence. Oncogenic: The B-RAFV600E variant is mentioned in the context of patients with B-RAF-mutated tumors, suggesting its role in tumor development or progression, which aligns with oncogenic evidence.
Gene→Variant (gene-first): 673:B-RAFV600E
Genes: 673
Variants: B-RAFV600E
TNBC cell lines (MDA-MB-231 and MDA-MB-468) with PIK3CA gene mutations (E545K and H1047R regions) and overexpression were established by transfection. NOD/SCID mice were used for in vivo experiments. Epirubicin was used
[Paragraph-level] PMCID: PMC8033310 Section: ABSTRACT PassageIndex: 4
Evidence Type(s): Oncogenic, Functional
Justification: Oncogenic: The passage discusses the establishment of TNBC cell lines with PIK3CA gene mutations (E545K and H1047R) and their use in in vivo experiments, indicating that these somatic variants contribute to tumor development or progression. Functional: The passage mentions the use of various assays (e.g., western blot, quantitative reverse transcription-polymerase chain reaction) to detect gene and protein expression levels, suggesting that the variants may alter molecular or biochemical function.
Gene→Variant (gene-first): 5290:E545K 5290:H1047R
Genes: 5290
Variants: E545K H1047R
The distribution pattern of the HER2 insertion mutations observed in our cohort was consistent with prior literature. The HER2 Y772_A775dupYVMA mutation was the most frequent and occurred in 65 (72.2%) patients, of whom
[Paragraph-level] PMCID: PMC8887939 Section: RESULTS PassageIndex: 11
Evidence Type(s): Predictive, Diagnostic
Justification: Predictive: The passage discusses the overall response rate (ORR) and median progression-free survival (PFS) associated with the HER2 insertion mutations, indicating a correlation with treatment response. Diagnostic: The mention of the frequency of the HER2 Y772_A775dupYVMA mutation in patients suggests its role in defining or classifying a specific disease subtype.
Gene→Variant (gene-first): 2064:A775dupYVMA 2064:G776delinsVC
Genes: 2064
Variants: A775dupYVMA G776delinsVC
KRAS G12D-mutant/p53-deficient non-small-cell lung cancer (NSCLC) models are dependent on the NF-kappaB pathway that can be down-regulated by the proteasome inhibitor bortezomib. Two exceptional responders were observed
[Paragraph-level] PMCID: PMC6549573 Section: ABSTRACT PassageIndex: 1
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the correlation between the KRAS G12D mutation and response to the therapy bortezomib, indicating that exceptional responses can be achieved in patients with this mutation. Oncogenic: The KRAS G12D mutation is described as a somatic variant that contributes to tumor development in non-small-cell lung cancer (NSCLC) models, indicating its role in oncogenesis.
Gene→Variant (gene-first): 3845:G12D
Genes: 3845
Variants: G12D
In the TAS6417 structure, the tricyclic core of the inhibitor forms dual hydrogen bonds to the kinase hinge, and the acrylamide forms the expected covalent bond with C797 (Fig. 4F). The quinoline substituent extends into
[Paragraph-level] PMCID: PMC11551396 Section: RESULTS PassageIndex: 18
Evidence Type(s): Functional
Justification: Functional: The passage discusses how the variant C797 interacts with the inhibitor at a molecular level, specifically forming covalent bonds and influencing the binding interactions within the kinase structure.
Gene→Variant (gene-first): 1956:C797 1956:T790
Genes: 1956
Variants: C797 T790
The core of TAK-788, which is identical to osimertinib, binds in essentially the same manner as osimertinib and the additional isopropyl ester of TAK-788 extends into the back pocket alongside the gatekeeper T790 and sim
[Paragraph-level] PMCID: PMC11551396 Section: RESULTS PassageIndex: 17
Evidence Type(s): Functional, Predictive
Justification: Functional: The passage discusses how the variant T790 interacts with the drug TAK-788, specifically mentioning hydrogen bonding and binding modes, indicating an alteration in molecular function. Predictive: The mention of TAK-788 binding to T790 suggests a correlation with therapeutic response, as it implies that the presence of T790 may influence the effectiveness of the treatment.
Gene→Variant (gene-first): 1956:T790
Genes: 1956
Variants: T790
Poziotinib is an anilinoquinazoline inhibitor and binds in the manner expected for this compound class, with a single hydrogen bond to the hinge region, and the halogen-substituted aniline group in the back pocket adjace
[Paragraph-level] PMCID: PMC11551396 Section: RESULTS PassageIndex: 16
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses how the C797 variant forms a covalent bond with the inhibitor, indicating an alteration in molecular function related to drug binding. Oncogenic: The T790M and V948R variants are described in the context of adopting an inactive kinase conformation, which suggests their role in tumor progression or development.
Gene→Variant (gene-first): 1956:C797 1956:T790M 1956:V948R
Genes: 1956
Variants: C797 T790M V948R
BAY-33 binds with its pyridine group adjacent to the hinge region of the kinase, where it forms a single hydrogen bond with the backbone amide of M793 (Fig. 4 A and B). The fluoro- and methoxy- substituted anilino group
[Paragraph-level] PMCID: PMC11551396 Section: RESULTS PassageIndex: 15
Evidence Type(s): None
Justification: Not enough information in this passage.
Gene→Variant (gene-first): 1956:T790
Genes: 1956
Variants: T790
As we have been unable to obtain suitable crystals of the insASV or insSVD variants, we determined cocrystal structures of BAY-33, TAK-788, TAS6417, and poziotinib with WT EGFR to better understand their binding modes an
[Paragraph-level] PMCID: PMC11551396 Section: RESULTS PassageIndex: 14
Evidence Type(s): None
Justification: Not enough information in this passage.
Gene→Variant (gene-first): 1956:T790M 1956:V948R
Genes: 1956
Variants: T790M V948R
To better understand the degree of correlation in drug sensitivity across WT and various EGFR mutants, we plotted pairwise comparisons of IC50 values (Fig. 2). This analysis revealed little if any correlation in inhibito
[Paragraph-level] PMCID: PMC11551396 Section: RESULTS PassageIndex: 9
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the correlation between the L858R variant and drug sensitivity, indicating that the L858R mutation has a drug-sensitizing effect, which aligns with predictive evidence regarding therapy response. Oncogenic: The L858R variant is implicated in greater potency against EGFR compared to WT EGFR, suggesting its role in tumor development or progression, which is characteristic of oncogenic evidence.
Gene→Variant (gene-first): 1956:L858R
Genes: 1956
Variants: L858R
We measured the biochemical potencies of a diverse panel of EGFR inhibitors against insASV, insSVD, and insNPG exon 20 insertion mutants and for comparison against WT EGFR and the L858R and L858R/T790M point mutants. Inh
[Paragraph-level] PMCID: PMC11551396 Section: RESULTS PassageIndex: 7
Evidence Type(s): Predictive, Functional
Justification: Predictive: The passage discusses the measurement of biochemical potencies of EGFR inhibitors against specific mutants, including L858R and L858R/T790M, indicating a correlation with response to therapy. Functional: The passage describes the use of recombinant EGFR kinase proteins in assays to evaluate the biochemical activity of inhibitors, which implies that the variants may alter molecular function.
Gene→Variant (gene-first): 1956:L858R 1956:T790M
Genes: 1956
Variants: L858R T790M
The enhanced inhibitor sensitivity of EGFR L858R and exon 19 deletions stems, at least in part, from their decreased affinity for ATP compared to the WT EGFR. While the Km, ATP values of insASV and insSVD are higher as c
[Paragraph-level] PMCID: PMC11551396 Section: RESULTS PassageIndex: 5
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the enhanced inhibitor sensitivity of the L858R variant in relation to its decreased affinity for ATP, indicating a correlation with sensitivity to EGFR TKIs, which aligns with predictive evidence. Oncogenic: The passage implies that the L858R variant contributes to oncogenicity, as it discusses the variant's biochemical properties and their relation to tumor development and progression.
Gene→Variant (gene-first): 1956:L858R
Genes: 1956
Variants: L858R
We used a coupled enzyme assay to determine enzyme kinetic parameters for these exon 20 insertions, as well as for WT, L858R, and L858R/T790M EGFR for comparison. This well-established continuous assay employs pyruvate k
[Paragraph-level] PMCID: PMC11551396 Section: RESULTS PassageIndex: 4
Evidence Type(s): Functional
Justification: Functional: The passage discusses enzyme kinetic parameters and catalytic efficiencies of the L858R variant and other variants, indicating that these variants alter molecular function as demonstrated by the enzyme assays.
Gene→Variant (gene-first): 7294:Glu4 1956:L858R 1956:T790M
Genes: 7294 1956
Variants: Glu4 L858R T790M
After transfection, the cells were allowed to grow for 24 h and then lysed. The level of EGFR-mCherry and wild-type and S310F HER2-eGFP in the cell lysate was determined by measuring the fluorescence intensity. After a c
[Paragraph-level] PMCID: PMC6843359 Section: RESULTS PassageIndex: 11
Evidence Type(s): Functional
Justification: Functional: The passage discusses how the S310F variant of HER2 interacts with EGFR and compares its efficiency to wild-type HER2, indicating an alteration in molecular function.
Gene→Variant (gene-first): 2064:S310F
Genes: 2064
Variants: S310F
Single molecule interaction analysis was performed to determine whether the S310F HER mutant formed a heterodimer with the EGFR. We constructed a bicistronic mammalian expression vector encoding EGFR-mCherry and S310F HE
[Paragraph-level] PMCID: PMC6843359 Section: RESULTS PassageIndex: 10
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses the interaction of the S310F HER2 mutant with EGFR and its altered reactivity to specific antibodies, indicating a change in molecular function. Oncogenic: The S310F HER2 variant is implicated in altered interactions that may contribute to tumor development or progression, as suggested by the context of the study involving cancer-related proteins.
Gene→Variant (gene-first): 2064:S310F
Genes: 2064
Variants: S310F
3.4. Single-Molecular Interaction Analysis Demonstrated That the S310F HER2 Mutant Formed Heterodimers with the EGFR
[Paragraph-level] PMCID: PMC6843359 Section: RESULTS PassageIndex: 9
Evidence Type(s): Functional
Justification: Functional: The passage indicates that the S310F variant alters the molecular interaction by forming heterodimers with EGFR, suggesting a change in biochemical function.
Gene→Variant (gene-first): 2064:S310F
Genes: 2064
Variants: S310F
We tested the effects of anti-HER2 agents on 5637 cell proliferation and the level of HER2 phosphorylation at Y1221 and Y1222 residues. The cells were incubated with pertuzumab, trastuzumab and lapatinib for 96 h, lysed
[Paragraph-level] PMCID: PMC6843359 Section: RESULTS PassageIndex: 8
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the effects of anti-HER2 agents on cell proliferation and HER2 phosphorylation in relation to the S310F HER2 mutant, indicating a correlation with response to specific therapies. Oncogenic: The S310F variant is implicated in the phosphorylation process and cell proliferation in cancer cells, suggesting its role in tumor development or progression.
Gene→Variant (gene-first): 2064:S310F
Genes: 2064
Variants: S310F
3.3. EGFR Activates S310F HER2 Mutant in 5637 Cell
[Paragraph-level] PMCID: PMC6843359 Section: RESULTS PassageIndex: 7
Evidence Type(s): Oncogenic
Justification: Oncogenic: The passage indicates that the S310F variant in HER2 is associated with activation in a cell line, suggesting its role in tumor development or progression.
Gene→Variant (gene-first): 2064:S310F
Genes: 2064
Variants: S310F
To confirm the expression of the S310F HER2 mutant in 5637 cells, we used immunoprecipitation experiments. We hypothesized that if the cells expressed the S310F HER2 mutant, it would not be immunoprecipitated by pertuzum
[Paragraph-level] PMCID: PMC6843359 Section: RESULTS PassageIndex: 6
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses the expression of the S310F HER2 mutant and its interaction with pertuzumab, indicating that the variant alters the molecular function of HER2 in terms of immunoprecipitation. Oncogenic: The S310F variant is described in the context of its expression in cancer cell lines, suggesting that it may contribute to tumor development or progression.
Gene→Variant (gene-first): 2064:S310F
Genes: 2064
Variants: S310F
We searched literatures to identify a human cell line expressing the S310F mutant and found that bladder cancer cell line 5637 expressed the mutant. To test the allelic expression of the S310F HER2 mutant in the 5637 cel
[Paragraph-level] PMCID: PMC6843359 Section: RESULTS PassageIndex: 5
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses the expression and detection of the S310F HER2 mutant in a bladder cancer cell line, indicating that the variant alters the molecular function of the HER2 protein as it is being analyzed for its presence on the cell surface. Oncogenic: The S310F variant is discussed in the context of a bladder cancer cell line, suggesting that it may contribute to tumor development or progression, which aligns with the definition of an oncogenic variant.
Gene→Variant (gene-first): 2064:S310 2064:S310F
Genes: 2064
Variants: S310 S310F
3.2. A Bladder Cancer Cell Line, 5637, Expresses Both Wild-Type HER2 and S310F Mutant
[Paragraph-level] PMCID: PMC6843359 Section: RESULTS PassageIndex: 4
Evidence Type(s): None
Justification: Not enough information in this passage.
Gene→Variant (gene-first): 2064:S310F
Genes: 2064
Variants: S310F
A construct encoding the S310F HER2 extracellular domain fused to a human Fc domain of immunoglobulin heavy chain was prepared and cloned into a mammalian expression vector. For comparison, the expression vectors encodin
[Paragraph-level] PMCID: PMC6843359 Section: RESULTS PassageIndex: 3
Evidence Type(s): Predictive, Functional
Justification: Predictive: The passage discusses the binding interactions of various HER2 mutants with the antibodies pertuzumab and trastuzumab, indicating their response to these therapies. Functional: The passage describes the preparation and purification of recombinant fusion proteins and their binding characteristics, which suggests alterations in molecular function related to the HER2 mutants.
Gene→Variant (gene-first): 2064:G309 2064:G309A 2064:G309E 2064:S309A 2064:S310 2064:S310F 2064:S310Y
Genes: 2064
Variants: G309 G309A G309E S309A S310 S310F S310Y
3.1. The Recombinant S310F Mutant Is Not Reactive to Pertuzumab but Binds to Trastuzumab
[Paragraph-level] PMCID: PMC6843359 Section: RESULTS PassageIndex: 2
Evidence Type(s): Predictive, Functional
Justification: Predictive: The passage indicates that the S310F mutant is not reactive to Pertuzumab, suggesting a correlation with resistance to this specific therapy. Functional: The passage discusses the binding characteristics of the S310F mutant, indicating an alteration in molecular function related to its interaction with Trastuzumab.
Gene→Variant (gene-first): 2064:S310F
Genes: 2064
Variants: S310F
KIT kinase V559D mutation is the most prevalent primary gain-of-function mutation in Gastrointestinal Stromal Tumors (GISTs). Here we reported a highly selective KIT V559D inhibitor CHMFL-KIT-031, which displayed about 1
[Paragraph-level] PMCID: PMC5762309 Section: ABSTRACT PassageIndex: 1
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the selective inhibitor CHMFL-KIT-031 and its efficacy against the KIT V559D mutation, indicating a correlation with response to therapy. Oncogenic: The KIT V559D mutation is described as a primary gain-of-function mutation in GISTs, suggesting it contributes to tumor development or progression.
Gene→Variant (gene-first): 3815:D816V 3815:L576P 3815:N822K 3815:T670I 3815:V559D 3815:V654A
Genes: 3815
Variants: D816V L576P N822K T670I V559D V654A
Recent advances in molecular profiling technologies allow genetic driver events in individual tumors to be identified. The hypothesis behind this ongoing molecular profiling effort is that improvement in patients' clinic
[Paragraph-level] PMCID: PMC5002925 Section: ABSTRACT PassageIndex: 1
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the treatment of a patient with advanced colorectal cancer using trastuzumab based on the presence of the ERBB2 p.L755S mutation, indicating a correlation with therapy response. Oncogenic: The mention of the ERBB2 p.L755S mutation as a genetic driver event in the context of advanced colorectal cancer suggests its role in tumor development or progression.
Gene→Variant (gene-first): 2064:p.L755S 673:p.N581S 324:p.Q1429fs
Genes: 2064 673 324
Variants: p.L755S p.N581S p.Q1429fs
In keeping with the identification of KRAS and/or NRAS mutations as the dominant genomic change associated with treatment resistance, serial ctDNA analysis was able to reveal the emergence of these mutations prior to dis
[Paragraph-level] PMCID: PMC10011885 Section: RESULTS PassageIndex: 24
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the emergence of KRAS mutations associated with treatment resistance, indicating a correlation with response to therapy, specifically in the context of chemotherapy and targeted treatments. Oncogenic: The passage describes the identification of KRAS mutations that contribute to tumor progression, particularly noting the emergence of these mutations prior to disease progression, which is indicative of their role in cancer development.
Gene→Variant (gene-first): 3791:A163G 3845:G12D 3845:G12N 3845:G13D 3845:Q61H 4893:Q61L 79811:R106H 673:V600E
Genes: 3791 3845 4893 79811 673
Variants: A163G G12D G12N G13D Q61H Q61L R106H V600E
Plasma DNA collected at the time of disease progression was analyzed through targeted sequencing to identify evidence of genomic evolution following treatment and potential mechanisms of acquired resistance to therapy. I
[Paragraph-level] PMCID: PMC10011885 Section: RESULTS PassageIndex: 23
Evidence Type(s): Oncogenic
Justification: Oncogenic: The passage discusses the retention of the BRAF V600E mutation in patients with mCRC, indicating its role in tumor development or progression, particularly in the context of disease progression and treatment response.
Gene→Variant (gene-first): 673:V600E
Genes: 673
Variants: V600E
The ratio of BRAF V600E mutation VAF on treatment at week 2 and week 4, relative to baseline was assessed as a predictor of PFS and OS. Most patients (19/21; 91%) had a week 2-baseline ratio (W2-BLR) of <1, with a median
[Paragraph-level] PMCID: PMC10011885 Section: RESULTS PassageIndex: 20
Evidence Type(s): Prognostic, Predictive
Justification: Prognostic: The passage discusses how the BRAF V600E mutation VAF ratio correlates with progression-free survival (PFS) and overall survival (OS), indicating that it is associated with disease outcomes independent of therapy. Predictive: The assessment of the BRAF V600E mutation VAF ratio as a predictor of PFS and OS suggests that it may correlate with treatment response, indicating its predictive value in the context of therapy.
Gene→Variant (gene-first): 673:V600E
Genes: 673
Variants: V600E
We next explored whether early, dynamic changes in ctDNA levels were predictive of outcomes to combination vemurafenib and erlotinib therapy. A total of 25 paired baseline-week 2 (BL-W2) and 21 paired baseline-week 4 (BL
[Paragraph-level] PMCID: PMC10011885 Section: RESULTS PassageIndex: 19
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses how early changes in ctDNA levels, specifically related to the BRAF V600E variant, are predictive of clinical benefit and objective response to combination vemurafenib and erlotinib therapy. Oncogenic: The BRAF V600E variant is implicated in tumor dynamics and is associated with the response to treatment, indicating its role in tumor development or progression.
Gene→Variant (gene-first): 673:V600E
Genes: 673
Variants: V600E
In addition to ddPCR testing, baseline plasma DNA was analyzed using a targeted capture based next-generation sequencing assay (Avenio Expanded panel, Roche Diagnostics; Supplementary Table S1 for list of genes). At leas
[Paragraph-level] PMCID: PMC10011885 Section: RESULTS PassageIndex: 16
Evidence Type(s): Predictive, Diagnostic, Oncogenic
Justification: Predictive: The passage indicates that the presence of genetic alterations, including the NRAS G13C mutation, correlates with clinical benefit from treatment, suggesting a predictive relationship regarding therapy response. Diagnostic: The mention of the NRAS G13C mutation being detected in a patient implies its role in identifying or classifying the disease, which aligns with diagnostic evidence. Oncogenic: The NRAS G13C mutation is discussed in the context of being a mutation found in a patient, which suggests its potential role in tumor development or progression.
Gene→Variant (gene-first): 4893:G13C
Genes: 4893
Variants: G13C
Twenty-five patients had serial plasma available for ctDNA analyses (Fig. 3A). Baseline pretreatment plasma DNA analyzed by droplet digital PCR (ddPCR) was positive for BRAF V600E mutant ctDNA in 21 of 25 patients (84%).
[Paragraph-level] PMCID: PMC10011885 Section: RESULTS PassageIndex: 15
Evidence Type(s): Diagnostic, Prognostic, Oncogenic
Justification: Diagnostic: The passage indicates that BRAF V600E mutant ctDNA is detected in a significant proportion of patients, suggesting its use in defining or confirming the presence of a specific disease. Prognostic: The passage states that higher levels of ctDNA at baseline are associated with inferior progression-free survival (PFS) and overall survival (OS), indicating a correlation with disease outcome independent of therapy. Oncogenic: The presence of the BRAF V600E variant in ctDNA suggests its role in tumor development or progression, as it is a known somatic mutation associated with cancer.
Gene→Variant (gene-first): 673:V600E
Genes: 673
Variants: V600E
A total of 40 patients were enrolled across the dose escalation and dose expansion phases (mCRC n = 33 and non-CRC cohort n = 7) between July 2014 and August 2017 (Fig. 1A). The non-colorectal cancer cohort included 7 pa
[Paragraph-level] PMCID: PMC10011885 Section: RESULTS PassageIndex: 3
Evidence Type(s): Diagnostic, Oncogenic
Justification: Diagnostic: The passage mentions that the non-colorectal cancer cohort included patients who were BRAF V600E mutation positive, indicating that this variant is used to classify or define a specific group of patients with selected cancers. Oncogenic: The BRAF V600E mutation is associated with tumor development in various cancers, as indicated by its presence in patients with selected cancers, suggesting its role in oncogenesis.
Gene→Variant (gene-first): 673:V600E
Genes: 673
Variants: V600E
Epidermal growth factor receptor (EGFR) exon 20 insertion mutations account for a tenth of all EGFR mutations in lung cancers. An important unmet clinical need is the identification of EGFR exon 20 insertion mutants that
[Paragraph-level] PMCID: PMC8700411 Section: ABSTRACT PassageIndex: 1
Evidence Type(s): Predictive, Diagnostic, Oncogenic
Justification: Predictive: The passage discusses the sensitivity of specific EGFR variants (D770 and G770) to various EGFR-TKIs, indicating a correlation with response to therapy. Diagnostic: The mention of EGFR exon 20 insertion mutations and their frequency in lung cancer suggests that these variants are used to classify and define a specific subtype of the disease. Oncogenic: The variants D770 and G770 are described as contributing to tumor development, as they are part of the EGFR mutations associated with lung cancer.
Gene→Variant (gene-first): 1956:D770 1956:G770 1956:Y764insFQEA
Genes: 1956
Variants: D770 G770 Y764insFQEA
Although these cases are limited in number and by reporting biases, they provide supporting evidence that EGFR-D770>GY and other exon 20 insertion mutations with G770 equivalence are sensitive to the clinically available
[Paragraph-level] PMCID: PMC8700411 Section: RESULTS PassageIndex: 13
Evidence Type(s): Predictive
Justification: Predictive: The passage indicates that the variant G770 and other exon 20 insertion mutations are sensitive to specific EGFR TKIs, suggesting a correlation with treatment response.
Gene→Variant (gene-first): 1956:G770
Genes: 1956
Variants: G770
The majority:but not all:of cases that received poziotinib or mobocertinib in this compiled cohort of advanced lung cancers harboring EGFR exon 20 insertion mutations with G770 equivalence had radiographic responses (Tab
[Paragraph-level] PMCID: PMC8700411 Section: RESULTS PassageIndex: 12
Evidence Type(s): Predictive, Diagnostic
Justification: Predictive: The passage discusses the correlation between the G770 variant and radiographic responses to therapies (poziotinib and mobocertinib) in advanced lung cancers, indicating its predictive nature regarding treatment response. Diagnostic: The mention of "EGFR exon 20 insertion mutations with G770 equivalence" suggests that the G770 variant is used to classify or define a specific subtype of lung cancer, supporting its role as a diagnostic marker.
Gene→Variant (gene-first): 1956:G770
Genes: 1956
Variants: G770
We identified seven reports from the literature and added one case from our institutional cohort that detailed partial clinical-radiographic parameters in patients with metastatic lung cancers harboring EGFR exon 20 inse
[Paragraph-level] PMCID: PMC8700411 Section: RESULTS PassageIndex: 10
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the response of patients with metastatic lung cancers harboring EGFR exon 20 insertion mutations, including G770, to various EGFR TKIs, indicating a correlation with treatment response. Oncogenic: The mention of tumors harboring EGFR exon 20 insertion mutations, including G770, suggests that this somatic variant contributes to tumor development or progression in the context of metastatic lung cancers.
Gene→Variant (gene-first): 1956:G770
Genes: 1956
Variants: G770
3.3. Clinical Outcomes of Reported Patients with Advanced Lung Cancers Harboring EGFR Exon 20 Insertion Mutations Encompassing G770 Equivalence
[Paragraph-level] PMCID: PMC8700411 Section: RESULTS PassageIndex: 9
Evidence Type(s): Diagnostic, Oncogenic
Justification: Diagnostic: The passage discusses patients with advanced lung cancers harboring EGFR Exon 20 insertion mutations, indicating that the variant is used to classify or define a specific disease subtype. Oncogenic: The mention of advanced lung cancers suggests that the G770 variant contributes to tumor development or progression, aligning with the definition of an oncogenic variant.
Gene→Variant (gene-first): 1956:G770
Genes: 1956
Variants: G770
Our aforementioned preclinical results confirmed the structural modeling of EGFR-D770>GY (Figure 1A) and led us to speculate that patients with advanced lung cancers harboring EGFR exon 20 insertion mutations with a G770
[Paragraph-level] PMCID: PMC8700411 Section: RESULTS PassageIndex: 8
Evidence Type(s): Predictive
Justification: Predictive: The passage discusses the potential response of patients with advanced lung cancers harboring the G770 variant to specific therapies, indicating a correlation with treatment response.
Gene→Variant (gene-first): 1956:G770
Genes: 1956
Variants: G770
The exquisite sensitivity to 2nd generation EGFR TKIs was confirmed at the biochemical level. In Western blot experiments, the phosphorylated form of EGFR was readily inhibited by 10 nM and higher doses of dacomitinib in
[Paragraph-level] PMCID: PMC8700411 Section: RESULTS PassageIndex: 7
Evidence Type(s): Predictive, Functional
Justification: Predictive: The passage discusses the sensitivity of the V769dupASV variant to 2nd generation EGFR TKIs, indicating a correlation with response to therapy. Functional: The variant V769dupASV is shown to alter the biochemical function of EGFR, as evidenced by the differing levels of inhibition of phosphorylated EGFR in response to dacomitinib.
Gene→Variant (gene-first): 1956:V769dupASV
Genes: 1956
Variants: V769dupASV
To highlight the differences in proliferation assays between Ba/F3 cells driven by the EGFR-D770>GY mutant and the more typical EGFR-A767_V769dupASV mutant, we show the dose-response curve for increasing concentrations o
[Paragraph-level] PMCID: PMC8700411 Section: RESULTS PassageIndex: 6
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the response of cells with the A767_V769dupASV mutant to specific therapies (afatinib and dacomitinib), indicating a correlation between the variant and treatment sensitivity. Oncogenic: The variant A767_V769dupASV is mentioned in the context of proliferation assays, suggesting that it contributes to tumor development or progression in the tested cell lines.
Gene→Variant (gene-first): 1956:V769dupASV
Genes: 1956
Variants: V769dupASV
Our group generated a Ba/F3 cell line driven by the EGFR-D770>GY mutant in order to compare its properties with our previously described isogenic Ba/F3 preclinical models of exon 20 insertion mutants (Figure 2). To evalu
[Paragraph-level] PMCID: PMC8700411 Section: RESULTS PassageIndex: 5
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the sensitivity and resistance of various EGFR mutations, including D770_N771insSVD, V769dupASV, and Y764insFQEA, to different EGFR TKIs, indicating a correlation with response to therapy. Oncogenic: The variants mentioned are associated with the development of cancer, as they are described in the context of a Ba/F3 cell line model driven by specific EGFR mutations, which contribute to tumor behavior.
Gene→Variant (gene-first): 1956:D770_N771insSVD 1956:V769dupASV 1956:Y764insFQEA
Genes: 1956
Variants: D770_N771insSVD V769dupASV Y764insFQEA
3.2. Preclinical Characterization of an EGFR Exon 20 Insertion Mutant with a G770 Equivalence
[Paragraph-level] PMCID: PMC8700411 Section: RESULTS PassageIndex: 4
Evidence Type(s): None
Justification: Not enough information in this passage.
Gene→Variant (gene-first): 1956:G770
Genes: 1956
Variants: G770
We queried three separate cohorts of EGFR exon 20 insertion mutations. Out of the 429 cases reported, 17 (3.96%) had the EGFR mutation leading to G770 equivalent change in the context of an insertion (Figure 1B). The typ
[Paragraph-level] PMCID: PMC8700411 Section: RESULTS PassageIndex: 3
Evidence Type(s): Diagnostic, Oncogenic
Justification: Diagnostic: The passage discusses the prevalence of the G770 variant in a cohort of cases with EGFR exon 20 insertion mutations, indicating its association with a specific mutation type and providing context for its classification. Oncogenic: The mention of the G770 variant in the context of EGFR mutations suggests its role in tumor development or progression, as it is part of a known oncogenic pathway associated with cancer.
Gene→Variant (gene-first): 1956:G770
Genes: 1956
Variants: G770
3.1. Frequency of EGFR Exon 20 Insertions with a G770 Equivalence
[Paragraph-level] PMCID: PMC8700411 Section: RESULTS PassageIndex: 2
Evidence Type(s): Diagnostic
Justification: Diagnostic: The mention of "frequency" in relation to "EGFR Exon 20 Insertions with a G770 Equivalence" suggests that the variant is being used to classify or define a specific disease or subtype.
Gene→Variant (gene-first): 1956:G770
Genes: 1956
Variants: G770
In addition, the ADx-ARMS identified 2 samples with both 19 del and L858R mutation, 4 with both 19 del and T790M mutation, and 1 with both L858R and L861Q or S768I (The two spots were designed in one tube, we could not d
[Paragraph-level] PMCID: PMC3287118 Section: RESULTS PassageIndex: 7
Evidence Type(s): None
Justification: Not enough information in this passage.
Gene→Variant (gene-first): 1956:L858R 1956:L861Q 1956:S768I 1956:T790M
Genes: 1956
Variants: L858R L861Q S768I T790M
These updated results confirm the substantial clinical benefit and manageable toxicity of dabrafenib plus trametinib in BRAF V600E-mutant ATC. Dabrafenib plus trametinib notably improved long-term survival and represents
[Paragraph-level] PMCID: PMC9338780 Section: ABSTRACT PassageIndex: 8
Evidence Type(s): Predictive, Prognostic
Justification: Predictive: The passage discusses the clinical benefit of dabrafenib plus trametinib in BRAF V600E-mutant ATC, indicating a correlation with improved treatment response. Prognostic: The mention of improved long-term survival in patients with BRAF V600E-mutant ATC suggests a correlation with disease outcome independent of therapy.
Gene→Variant (gene-first): 673:V600E
Genes: 673
Variants: V600E
ROAR (NCT02034110) is an open-label, nonrandomized, phase II basket study evaluating dabrafenib plus trametinib in BRAF V600E-mutant rare cancers. The ATC cohort comprised 36 patients with unresectable or metastatic ATC
[Paragraph-level] PMCID: PMC9338780 Section: ABSTRACT PassageIndex: 4
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the evaluation of dabrafenib plus trametinib in patients with BRAF V600E-mutant cancers, indicating a correlation with treatment response. Oncogenic: The mention of BRAF V600E in the context of a study for rare cancers suggests that this somatic variant contributes to tumor development or progression.
Gene→Variant (gene-first): 673:V600E
Genes: 673
Variants: V600E
Combined therapy with dabrafenib plus trametinib was approved in several countries for treatment of BRAF V600E-mutant anaplastic thyroid cancer (ATC) based on an earlier interim analysis of 23 response-assessable patient
[Paragraph-level] PMCID: PMC9338780 Section: ABSTRACT PassageIndex: 2
Evidence Type(s): Predictive, Diagnostic
Justification: Predictive: The passage discusses the approval of combined therapy with dabrafenib plus trametinib for treatment of BRAF V600E-mutant anaplastic thyroid cancer, indicating a correlation with treatment response. Diagnostic: The mention of BRAF V600E as a specific mutation in anaplastic thyroid cancer suggests its role in defining or classifying the disease subtype.
Gene→Variant (gene-first): 673:V600E
Genes: 673
Variants: V600E
The present results suggested that acquired VOPP1-EGFR fusion gene with T790M potentially serve an additional resistance mechanism to first-generation EGFR tyrosine kinase inhibitors in EGFR-mutated NSCLC. And the presen
[Paragraph-level] PMCID: PMC8727519 Section: ABSTRACT PassageIndex: 6
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses T790M as a resistance mechanism to first-generation EGFR tyrosine kinase inhibitors, indicating its correlation with treatment response. Oncogenic: The mention of T790M in the context of an acquired resistance mechanism suggests that it contributes to tumor progression in EGFR-mutated NSCLC.
Gene→Variant (gene-first): 1956:T790M
Genes: 1956
Variants: T790M
In this case report, we describe a 69-year-old female who received right lobectomy and was diagnosed with pathological stage IIIA lung adenocarcinoma harboring EGFR L858R. Twenty months later he had recurrent disease in
[Paragraph-level] PMCID: PMC8727519 Section: ABSTRACT PassageIndex: 4
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the T790M variant as a potential resistance mechanism to icotinib treatment, indicating its correlation with treatment response. Oncogenic: The L858R variant is described as being present in a patient with lung adenocarcinoma, suggesting its role in tumor development or progression.
Gene→Variant (gene-first): 1956:L858R 1956:T790M
Genes: 1956
Variants: L858R T790M
Taletrectinib continues to show high and durable overall responses, prolonged PFS, robust activity against intracranial lesions and acquired resistance mutations including G2032R, and a favorable safety profile with a lo
[Paragraph-level] PMCID: PMC11272140 Section: ABSTRACT PassageIndex: 8
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the variant G2032R in the context of acquired resistance mutations and mentions the overall responses and prolonged progression-free survival (PFS) associated with taletrectinib, indicating a correlation with treatment response. Oncogenic: The mention of G2032R as an acquired resistance mutation suggests that it contributes to tumor development or progression, particularly in the context of therapy resistance.
Gene→Variant (gene-first): 6098:G2032R
Genes: 6098
Variants: G2032R
As of November 2023, 173 patients were enrolled (median age, 55 years; 58% female; 73% never smoked; TKI naive: n = 106; crizotinib pretreated: n = 67). In TKI-naive patients, cORR and intracranial cORR were 91% and 88%,
[Paragraph-level] PMCID: PMC11272140 Section: ABSTRACT PassageIndex: 6
Evidence Type(s): Predictive
Justification: Predictive: The passage indicates that 67% of patients with G2032R mutations responded to treatment, suggesting a correlation between the variant and treatment response.
Gene→Variant (gene-first): 6098:G2032R
Genes: 6098
Variants: G2032R
Taletrectinib, a highly potent, CNS-active, ROS1 tyrosine kinase inhibitor (TKI), has demonstrated high and durable response rates, high intracranial objective response rate (ORR), prolonged progression-free survival (PF
[Paragraph-level] PMCID: PMC11272140 Section: ABSTRACT PassageIndex: 2
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the activity of taletrectinib against the G2032R variant, highlighting its correlation with high response rates and prolonged progression-free survival, indicating predictive evidence related to therapy response. Oncogenic: The mention of the G2032R variant in the context of ROS1+ non-small cell lung cancer suggests that it may contribute to tumor development or progression, aligning with oncogenic evidence.
Gene→Variant (gene-first): 6098:G2032R
Genes: 6098
Variants: G2032R
Some of the differences between the effects of tested inhibitors on activating FGFR variants (Figure 6) are consistent with observations from structural studies. Based on the crystal structure of FGFR1 KD V561M, the inte
[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 33
Evidence Type(s): Predictive, Functional
Justification: Predictive: The passage discusses the expected efficacy of the JNJ42756493 inhibitor towards the FGFR3 V555M variant, indicating a correlation with response to therapy based on structural interactions. Functional: The passage mentions the interactions of inhibitors within the ATP-binding pocket of the FGFR1 KD V561M variant, suggesting that the variant alters molecular function related to drug binding and efficacy.
Gene→Variant (gene-first): 2261:V555M 2260:V561M
Genes: 2261 2260
Variants: V555M V561M
We further compared the effect of the two most potent FGFR-specific inhibitors AZD4547 and JNJ42756493 on hotspot mutations K650E and N540K in NIH3T3 cell lines. As previously reported and shown in Supplementary Figure S
[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 32
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the effect of the K650E and N540K variants on the efficacy of FGFR-specific inhibitors, indicating a correlation with treatment response. Oncogenic: The variants K650E and N540K are discussed in the context of their impact on cellular transformation and response to inhibitors, suggesting their role in tumor development or progression.
Gene→Variant (gene-first): 2261:K650E 2261:N540K
Genes: 2261
Variants: K650E N540K
The impact of each mutation on drug binding is expressed as a fold-difference in Ki compared to the FGFR3 KD WT (Figure 6C). Highly activating R669G and, in particular, hotspot mutation K650E had moderate effects on the
[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 31
Evidence Type(s): Predictive, Functional
Justification: Predictive: The passage discusses how specific mutations, such as K650E, N540K, N540S, and V555M, affect the efficacy of various inhibitors, indicating a correlation with resistance or sensitivity to therapy. Functional: The passage describes how mutations like I538V and V555M alter the binding affinity and efficacy of inhibitors, which reflects changes in molecular function related to drug interactions.
Gene→Variant (gene-first): 2263:I538 2263:I538V 2261:K650E 2261:N540 2261:N540K 2261:N540S 2261:R669G 2261:V555M
Genes: 2263 2261
Variants: I538 I538V K650E N540 N540K N540S R669G V555M
We performed measurements of Ki for AZD4547, BGJ-398, TKI258, JNJ42756493 and AP24534 using purified FGFR3 KD WT and variants R669G, K650E, N540S, N540K, V555M and I538V (Figure 6, Supplementary Table S3). Ki values for
[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 30
Evidence Type(s): Predictive, Functional
Justification: Predictive: The passage discusses the Ki values of various FGFR3 variants in response to specific inhibitors, indicating a correlation between the variants and their sensitivity to therapy. Functional: The mention of mutations affecting the ATP binding pocket and potential allosteric effects suggests that these variants alter the molecular function of the FGFR3 protein.
Gene→Variant (gene-first): 2263:I538V 2261:K650E 2261:N540K 2261:N540S 2261:R669G 2261:V555M
Genes: 2263 2261
Variants: I538V K650E N540K N540S R669G V555M
It is well established that some acquired mutations in protein kinases greatly reduce drug binding; the best-illustrated examples are gatekeeper mutations also described in FGFR3 (V555M). The question of how primary muta
[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 29
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses how mutations in protein kinases, such as V555M, can affect drug binding and implies a relationship between these mutations and drug efficacy, indicating a potential impact on treatment response. Oncogenic: The mention of V555M as an acquired mutation in FGFR3 suggests its role in tumor development or progression, particularly in the context of drug resistance.
Gene→Variant (gene-first): 2261:V555M
Genes: 2261
Variants: V555M
JNJ42756493 occupies the ATP-binding cleft of FGFR1 largely as expected on the basis of previous complexes between FGFR1 and other type-I inhibitors (e. g. BJG-398, AZD4547, PD173074 and TKI258) and where the activation
[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 27
Evidence Type(s): Functional
Justification: Functional: The passage discusses how the variants D641, L630, and V561 are involved in the binding interactions of the drug JNJ42756493 with FGFR1, indicating that these variants alter molecular interactions and contribute to the binding strength and specificity of the drug.
Gene→Variant (gene-first): 2260:D641 2260:L630 2260:V561
Genes: 2260
Variants: D641 L630 V561
Previous structural studies of FGFR2 KD highlighted a long-range allosteric communication linking the kinase hinge, the alphaC-helix and the A-loop. It was also illustrated that some A-loop mutations (such as FGFR3 K650E
[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 24
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses how the K650E, R675G, and R669G mutations alter the allosteric communication and molecular interactions within the FGFR kinases, indicating a change in molecular function. Oncogenic: The mention of mutations that force an active conformation and alter the position of the alphaC-helix suggests that these variants contribute to tumor development or progression.
Gene→Variant (gene-first): 2261:K650E 2261:R669G 2260:R675 2260:R675G
Genes: 2261 2260
Variants: K650E R669G R675 R675G
To gain further insight into the activation mechanism of the R669G mutation in FGFR3, we performed NMR studies in which we compared the backbone amide chemical shift perturbations (CSPs) associated with the R669G mutatio
[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 23
Evidence Type(s): Functional
Justification: Functional: The passage discusses how the R669G mutation alters molecular interactions and conformational changes in the FGFR3 protein, indicating an alteration in biochemical function.
Gene→Variant (gene-first): 2261:R669G
Genes: 2261
Variants: R669G
Comparison of this new FGFR1 R675G KD structure (Figure 4C, top) with inactive (apo) FGFR1 KD (PDB: 4UWY) and active, FGFR1-3P (pdb 3GQI) (Figure 4C, bottom) structures shows that FGFR1 R675G KD differs from the inactive
[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 22
Evidence Type(s): Functional
Justification: Functional: The passage describes how the R675G variant alters the molecular interactions and conformation of the FGFR1 kinase domain, indicating a change in biochemical function.
Gene→Variant (gene-first): 2261:H650 2260:R675 2260:R675G 2263:Y653
Genes: 2261 2260 2263
Variants: H650 R675 R675G Y653
The residue corresponding to R669 in FGFR3 is conserved and also mutated in all other FGFRs in cancer as well as in FGFR2 in bone dysplasia (Supplementary Table S1). To assess the mechanism that underpins activation, we
[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 21
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses the R to G replacement and its impact on the activity of the FGFR1 KD variant, indicating that the variant alters molecular function. Oncogenic: The mention of the R669 and R675G variants being mutated in cancer suggests their contribution to tumor development or progression.
Gene→Variant (gene-first): 2260:R to G 2261:R669 2260:R675G
Genes: 2260 2261
Variants: R to G R669 R675G
Activation mechanism of FGFR3 R669G mutation
[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 20
Evidence Type(s): Functional
Justification: Functional: The passage discusses the activation mechanism of the FGFR3 R669G mutation, indicating that it alters molecular or biochemical function.
Gene→Variant (gene-first): 2261:R669G
Genes: 2261
Variants: R669G
Comparison of our experimental data (Figure 2) with the assessments obtained using bioinformatics tools (Supplementary Table S1B and S1C) suggests that considering multiple methods together can provide insight into the i
[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 19
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses how the variants E466K, D617G, and G637W are predicted to reduce protein production or completely inactivate the kinase, indicating an alteration in molecular function. Oncogenic: The mention of R669 being within an identified cluster of observed A-loop cancer mutations suggests that it contributes to tumor development or progression.
Gene→Variant (gene-first): 2261:D617G 2263:E466K 2260:G637W 2261:R669
Genes: 2261 2263 2260
Variants: D617G E466K G637W R669
Analysis of the FGFR3 R669G NIH3T3 cell line has shown that despite low expression levels, downstream signaling appeared to be enhanced as well as FGFR3 phosphorylation (Figure 4A).
[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 18
Evidence Type(s): Functional
Justification: Functional: The passage discusses how the R669G variant alters downstream signaling and FGFR3 phosphorylation, indicating a change in molecular function.
Gene→Variant (gene-first): 2261:R669G
Genes: 2261
Variants: R669G
It could be expected that some mutations that map to the KD do not affect kinase activity directly as measured under conditions in vitro. In particular, the hotspot G697C mutation which does not have an effect in such as
[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 17
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses how the G697C mutation does not affect kinase activity directly as measured in vitro, indicating that it alters molecular function, specifically FGFR3 function, which can only be detected in a cellular setting. Oncogenic: The comparison of the FGFR3 G697C cell line with those expressing K650E and N540K shows that G697C does not lead to a transformed phenotype or anchorage-independent growth, suggesting it does not contribute to tumor development or progression like the other variants.
Gene→Variant (gene-first): 2261:G697C 2261:K650E 2261:N540K
Genes: 2261
Variants: G697C K650E N540K
From these direct measurements of kinase activity it seems that a considerable number of mutations reported so far result in kinase activation to some degree and that replacements that cause activation are not limited to
[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 16
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses how the K650E variant alters kinase activity, indicating a change in molecular function related to activation. Oncogenic: The mention of the K650E variant in the context of kinase activation suggests its potential role in tumor development or progression.
Gene→Variant (gene-first): 2261:K650E
Genes: 2261
Variants: K650E
Two mutations, D617G and G637W, completely abolished kinase activity (Figure 2A and 2B, bottom panel). Both residues are strongly conserved among protein kinases and some of the replacements of these residues in various
[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 15
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses how the mutations D617G and G637W abolish kinase activity, indicating that these variants alter the molecular function of the protein. Oncogenic: The passage mentions that the importance of these inactivating mutations for cancer development remains unclear, suggesting a potential role in tumor development or progression.
Gene→Variant (gene-first): 2261:D617 2261:D617G 2261:G to W 2260:G637 2260:G637W
Genes: 2261 2260
Variants: D617 D617G G to W G637 G637W
Twelve out of 26 analyzed mutations had very little or no effect on FGFR3 KD activity (Figure 2A and 2B, bottom panel). The number of observations in cancer for most of these mutations is low with the exception of G697C
[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 14
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses the effect of the G697C mutation on FGFR3 KD activity, indicating that it alters molecular function. Oncogenic: The mention of G697C as one of the hotspots suggests its potential role in tumor development or progression, which aligns with oncogenic behavior.
Gene→Variant (gene-first): 2261:G697C
Genes: 2261
Variants: G697C
Several other mutations, including V555M, D641G and D641N resulted in an increase of auto-phosphorylation up to 7-fold (Figure 2A) and a similar increase in substrate phosphorylation (Figure 2B, middle panel). The V555M
[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 13
Evidence Type(s): Predictive, Functional
Justification: Predictive: The V555M mutation is described as an acquired resistance mutation to an FGFR inhibitor, indicating a correlation with resistance to therapy. Functional: The passage discusses how the mutations, including V555M, D641G, and D641N, resulted in an increase in auto-phosphorylation and substrate phosphorylation, indicating an alteration in molecular function.
Gene→Variant (gene-first): 2260:D641G 2260:D641N 2261:V555 2261:V555M
Genes: 2260 2261
Variants: D641G D641N V555 V555M
Isolated FGFR KDs undergo auto-phosphorylation on several tyrosine residues and this property correlates well with the kinase activity towards natural and synthetic substrates. We used purified proteins of 26 FGFR3 KD va
[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 12
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses how different mutations in FGFR3 KD variants affect auto-phosphorylation and kinase activity, indicating that these variants alter molecular function. Oncogenic: The context of the passage suggests that the mutations contribute to tumor development or progression by enhancing kinase activity, which is a characteristic of oncogenic variants.
Gene→Variant (gene-first): 2263:I538V 2261:K650E 2261:K650N 2261:N540K 2261:N540S 2261:R669G 2261:R669Q
Genes: 2263 2261
Variants: I538V K650E K650N N540K N540S R669G R669Q
The number of cancer mutations in FGFR KDs that have been comprehensively assessed for their functional impact is limited, with the most emphasis being on replacements at positions corresponding to FGFR3 K650 and mutatio
[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 11
Evidence Type(s): Functional
Justification: Functional: The passage discusses the functional impact of mutations at positions FGFR3 K650 and N540K, indicating that these variants are assessed for their effect on kinase activity.
Gene→Variant (gene-first): 2261:K650 2261:N540K
Genes: 2261
Variants: K650 N540K
A number of crystal structures of FGFR KD in non-phosphorylated and phosphorylated forms have been reported. The 3D-structures highlighted the features that undergo substantial changes and play a key role in the activati
[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 7
Evidence Type(s): Oncogenic
Justification: Oncogenic: The passage discusses FGFR3 cancer mutations, indicating that the variants K650, R669, N540, and I538 are associated with cancer, suggesting their role in tumor development or progression.
Gene→Variant (gene-first): 2263:I538 2261:K650 2261:N540 2261:R669
Genes: 2263 2261
Variants: I538 K650 N540 R669
Comparison of positions mutated in bone dysplasia in all FGFRs with those reported for FGFR3 in cancer (Figure 1B, bottom) highlighted common residues including I538, N540, K650 and R669. With respect to the secondary st
[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 6
Evidence Type(s): None
Justification: Not enough information in this passage.
Gene→Variant (gene-first): 2261:G697 2263:I538 2261:K650 2261:N540 2261:R669
Genes: 2261 2263
Variants: G697 I538 K650 N540 R669
It has been previously highlighted that a number of cancer mutations, in particular in FGFR2 and FGFR3, have also been described in various developmental syndromes such as bone dysplasia. Positions mutated in FGFR3 in th
[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 5
Evidence Type(s): Diagnostic, Oncogenic
Justification: Diagnostic: The passage discusses mutations in FGFR3, including K650 and N540, in the context of developmental syndromes such as bone dysplasia, indicating their association with specific disease states. Oncogenic: The mention of FGFR3 mutations, including K650 and N540, being prevalent in bladder cancer suggests that these somatic variants contribute to tumor development or progression.
Gene→Variant (gene-first): 2261:K650 2261:N540 2261:N540K
Genes: 2261
Variants: K650 N540 N540K
The intracellular portion (residues 397-806 for FGFR3) comprises the juxtamembrane region, KD and C-terminal regions. The number of observed mutations at each residue within the intracellular portion of FGFR3 was compile
[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 4
Evidence Type(s): Oncogenic, Functional
Justification: Oncogenic: The passage discusses frequently mutated positions in FGFR3, specifically K650, G697, and N540, indicating their involvement in cancer, which suggests they contribute to tumor development or progression. Functional: The passage describes the specific amino acid replacements at the mutated positions, indicating alterations in molecular function related to FGFR3, which can affect its activity in cancer.
Gene→Variant (gene-first): 2261:G697 2261:G697C 2261:K650 2261:N540
Genes: 2261
Variants: G697 G697C K650 N540
To elucidate the functional consequences of ETV6 alterations, we performed luciferase reporter assays using an ETV6-responsive reporter construct (pGL2-754TR) derived from the stromelysin-1 gene. In line with the role of
[Paragraph-level] PMCID: PMC3244026 Section: RESULTS PassageIndex: 9
Evidence Type(s): Functional, Diagnostic
Justification: Functional: The passage discusses how the ETV6 mutants (V345fs, N356fs, Y103fs, S105fs) are functionally inactive and lack transcriptional repression activity, indicating that these variants alter molecular function. Diagnostic: The passage mentions that ETV6-mutated cases have a characteristic gene expression signature and that all ETV6 mutant T-ALL samples were CD33 positive, suggesting that these variants are associated with a specific disease subtype.
Gene→Variant (gene-first): 2120:N356fs 2120:S105fs 2120:V345fs 2120:Y103fs
Genes: 2120
Variants: N356fs S105fs V345fs Y103fs
The ETV6 tumor suppressor gene is frequently translocated in lymphoid and myeloid hematopoietic tumors and encodes a transcriptional repressor with an N-terminal pointed (PNT) homodimerization domain and a C-terminal ETS
[Paragraph-level] PMCID: PMC3244026 Section: RESULTS PassageIndex: 8
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage describes how N-terminal and C-terminal truncating mutations in the ETV6 gene alter the expression of truncated protein products, indicating a change in molecular function. Oncogenic: The context of the mutations being associated with hematopoietic tumors suggests that these somatic variants contribute to tumor development or progression.
Gene→Variant (gene-first): 2120:N356fs 2120:S105fs 2120:V345fs 2120:Y103fs
Genes: 2120
Variants: N356fs S105fs V345fs Y103fs
NM_005648.4(ELOC):c.236A>G (p.Tyr79Cys) was originally described as a somatic variant in six RCCs without VHL inactivation, in three cases within The Cancer Genome Atlas and subsequently in five cases from the Memorial S
[Paragraph-level] PMCID: PMC9402235 Section: RESULTS PassageIndex: 9
Evidence Type(s): Oncogenic, Diagnostic
Justification: Oncogenic: The passage describes the NM_005648.4(ELOC):c.236A>G (p.Tyr79Cys) variant as a somatic variant found in renal cell carcinomas (RCCs) and indicates its role in VHL-independent renal tumorigenesis, supporting its contribution to tumor development. Diagnostic: The passage discusses the search for germline ELOC variants in individuals with a VHL-like phenotype and indicates that the NM_005648.4(ELOC):c.236A>G (p.Tyr79Cys) variant was absent in these individuals, suggesting its potential use in defining or excluding a disease or subtype.
Gene→Variant (gene-first): 3091:c.236A>G 6921:c.261_272del 5979:c.274G>A 6921:c.311T>A 3855:c.74A>T 3855:p.Asp25Val 7409:p.Glu92Lys 6921:p.Leu104Gln 6921:p.Thr88_Pro91del 3091:p.Tyr79Cys
Genes: 3091 6921 5979 3855 7409
Variants: c.236A>G c.261_272del c.274G>A c.311T>A c.74A>T p.Asp25Val p.Glu92Lys p.Leu104Gln p.Thr88_Pro91del p.Tyr79Cys
ELOC c.236A>G (p.Tyr79Cys) variation in human disease
[Paragraph-level] PMCID: PMC9402235 Section: RESULTS PassageIndex: 8
Evidence Type(s): None
Justification: Not enough information in this passage.
Gene→Variant (gene-first): 3091:c.236A>G 3091:p.Tyr79Cys
Genes: 3091
Variants: c.236A>G p.Tyr79Cys
Microarray-based comparative genomic hybridization (aCGH) performed on the DNA pair extracted from the proband's right RCC and blood showed evidence of monosomy for chromosomes 8, 21 and 22 and no somatic alterations wer
[Paragraph-level] PMCID: PMC9402235 Section: RESULTS PassageIndex: 6
Evidence Type(s): None
Justification: Not enough information in this passage.
Gene→Variant (gene-first): 3091:236A>G 3091:c.236A>G 3091:p.Tyr79Cys
Genes: 3091
Variants: 236A>G c.236A>G p.Tyr79Cys
Routine diagnostic testing by Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA) for a germline VHL variant showed no abnormality, and after informed written consent, the proband and her parent
[Paragraph-level] PMCID: PMC9402235 Section: RESULTS PassageIndex: 5
Evidence Type(s): Diagnostic, Functional
Justification: Diagnostic: The passage discusses the identification of a de novo missense variant in ELOC and its validation in the proband, indicating its potential role in defining or confirming a genetic condition. Functional: The passage describes the critical role of the Tyr79 residue in forming a hydrogen bond within the pVHL alpha domain, suggesting that the variant alters molecular function.
Gene→Variant (gene-first): 3091:Tyr79 3091:Y79 3091:c.236A>G 3091:p.Tyr79Cys
Genes: 3091
Variants: Tyr79 Y79 c.236A>G p.Tyr79Cys
In the retrospective cohort (n = 102), 14 samples were excluded due to insufficient coverage. Among the remaining 88 cases, 45 cases had mutations: 27 PIK3CA, 11 TEK (one with two mutations in cis, TEK: c.[2690A > G; c.2
[Paragraph-level] PMCID: PMC6594036 Section: RESULTS PassageIndex: 8
Evidence Type(s): None
Justification: Not enough information in this passage.
Gene→Variant (gene-first): 7010:2690A > G 3845:Arg918Cys 7010:Tyr897Cys 7010:c.2752A > G
Genes: 7010 3845
Variants: 2690A > G Arg918Cys Tyr897Cys c.2752A > G
The BRCA1 tumor suppressor gene encodes a multi-domain protein for which several functions have been described. These include a key role in homologous recombination repair (HRR) of DNA double-strand breaks (DSB), which i
[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
We examined Mig-6 expression in PC9 cells harboring the EGFR exon 19 deletion and PC9/GR cells, which have EGFR-TKI resistance with an acquired T790M mutation. Western blotting and immunofluorescence analyses showed that
[Paragraph-level] PMCID: PMC7302243 Section: RESULTS PassageIndex: 3
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the acquired T790M mutation in the context of EGFR-TKI resistance, indicating a correlation with treatment resistance. Oncogenic: The T790M mutation is described as contributing to EGFR-TKI resistance, which is a characteristic of tumor progression in the context of cancer.
Gene→Variant (gene-first): 1956:T790M
Genes: 1956
Variants: T790M
Activation of p110beta/p85alpha-nicSH2 and p110delta/p85alpha-nicSH2 complexes by phosphopeptide also induces lipid binding (Figure 5a). This is in agreement with the recent report for p110delta in a complex with full-le
[Paragraph-level] PMCID: PMC3378484 Section: RESULTS PassageIndex: 24
Evidence Type(s): Functional
Justification: Functional: The passage discusses how the variant H1047L alters the lipid binding capabilities of the p110alpha isoform, indicating a change in molecular function.
Gene→Variant (gene-first): 5290:H1047 5290:H1047L
Genes: 5290
Variants: H1047 H1047L
The p85alpha nSH2 does not contact the lipid binding elements in the kinase C-lobe (Figure 4a) but appears to control their access to membrane (Figure 3f-j). This suggests the activation mechanism by nSH2 to be allosteri
[Paragraph-level] PMCID: PMC3378484 Section: RESULTS PassageIndex: 22
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses how the H1047R variant leads to a global conformational change in the p110alpha/p85alpha structure, suggesting that it alters molecular function and potentially impacts activity. Oncogenic: The context implies that the H1047R variant contributes to tumor development or progression through its role in altering the conformational dynamics of the kinase, which is relevant in cancer biology.
Gene→Variant (gene-first): 5290:H1047R
Genes: 5290
Variants: H1047R
For non-kinase domain mutants, the nature of the effects of hydrophobicity is not immediately obvious. Disruption of the C2-iSH2 (C420R and p85alpha-N564D) or the C2/helical-nSH2 contacts (E545K) could expose hydrophobic
[Paragraph-level] PMCID: PMC3378484 Section: RESULTS PassageIndex: 20
Evidence Type(s): Functional
Justification: Functional: The passage discusses how the variants C420R and N564D alter the molecular interactions within the C2 domain, suggesting changes in lipid binding capabilities, which indicates an alteration in biochemical function.
Gene→Variant (gene-first): 5290:C420 5290:C420R 5290:E545K 5295:N345 5295:N564 5295:N564D
Genes: 5290 5295
Variants: C420 C420R E545K N345 N564 N564D
Despite their different chemical properties, the kinase domain mutants, H1047L, H1047R and G1049R, exhibit similarly high levels of hydrophobic binding to neutral lipids, and electrostatic binding to PS/PtdIns(4,5)P2-con
[Paragraph-level] PMCID: PMC3378484 Section: RESULTS PassageIndex: 19
Evidence Type(s): Functional
Justification: Functional: The passage discusses how the variants G1049R, H1047L, and H1047R alter binding properties to lipids, indicating a change in molecular function related to lipid binding upon activation.
Gene→Variant (gene-first): 5290:G1049R 5290:H1047L 5290:H1047R
Genes: 5290
Variants: G1049R H1047L H1047R
There is a pattern correlating the location of the mutations with their hydrophobic component of lipid binding (Figure 3j): non-kinase domain mutants (C420R, E545K and p85alpha-N564D) display high levels of hydrophobic i
[Paragraph-level] PMCID: PMC3378484 Section: RESULTS PassageIndex: 18
Evidence Type(s): Functional
Justification: Functional: The passage discusses how the mutations (C420R, E545K, and N564D) alter the hydrophobic interaction with neutral lipids, indicating a change in molecular function related to lipid binding.
Gene→Variant (gene-first): 5290:C420R 5290:E545K 5295:N564D
Genes: 5290 5295
Variants: C420R E545K N564D
Overall, there is a strong correlation between lipid kinase activity and lipid binding (Figure 3i,j, total lipid binding on Fc4 is shown in Supplementary Figure S3), underscoring enhanced lipid binding as a general mecha
[Paragraph-level] PMCID: PMC3378484 Section: RESULTS PassageIndex: 17
Evidence Type(s): Functional
Justification: Functional: The passage discusses how the E545K variant alters lipid kinase activity and lipid binding, indicating a change in molecular function.
Gene→Variant (gene-first): 5290:E545K
Genes: 5290
Variants: E545K
To gain a broader view of the effects of cancer-linked mutations, we studied seven mutations that have previously been characterized to be activating. They cover three structurally distinct regions (Figure 3a-c), namely,
[Paragraph-level] PMCID: PMC3378484 Section: RESULTS PassageIndex: 16
Evidence Type(s): Oncogenic
Justification: Oncogenic: The passage discusses mutations that are characterized as activating, indicating that they contribute to tumor development or progression.
Gene→Variant (gene-first): 5290:C420R 5290:E545K 5290:G1049R 5290:H1047L 5290:H1047R 5290:M1043I 5295:N564D
Genes: 5290 5295
Variants: C420R E545K G1049R H1047L H1047R M1043I N564D
Using PtdIns(4,5)P2-containing liposomes, no kinase activity could be detected for three engineered kinase domain mutants: (i) the activation loop mutant R949D, (ii) the kinase helix kalpha12 deletion mutant (Deltacterm)
[Paragraph-level] PMCID: PMC3378484 Section: RESULTS PassageIndex: 14
Evidence Type(s): Functional
Justification: Functional: The passage discusses how the K942Q and R949D variants alter molecular function, specifically their effects on kinase activity and lipid binding, indicating changes in biochemical properties.
Gene→Variant (gene-first): 5294:K942Q 5294:R949D
Genes: 5294
Variants: K942Q R949D
To test whether lipid binding forms the basis of p110 activation, we compared lipid kinase with lipid binding activities for three sets of p110alpha/p85alpha complexes: SH2 deletions in p85alpha, engineered mutations in
[Paragraph-level] PMCID: PMC3378484 Section: RESULTS PassageIndex: 9
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses the D915N mutation in the context of its role in lipid binding and activation of p110alpha, indicating that it alters molecular function related to protein activity. Oncogenic: The mention of "cancer-linked mutations" suggests that the D915N variant is associated with tumor development or progression, as it is discussed in the context of p110alpha, which is implicated in cancer.
Gene→Variant (gene-first): 5290:D915N
Genes: 5290
Variants: D915N
Deletion of helix kalpha12 in Vps34, p110beta and p110delta abrogated lipid kinase activity and lipid binding. This region is also of functional importance for p110alpha (see below). Deletion of kalpha12 in Vps34 and in
[Paragraph-level] PMCID: PMC3378484 Section: RESULTS PassageIndex: 7
Evidence Type(s): Functional
Justification: Functional: The passage discusses how the deletion of residues 1051-1068 alters the lipid kinase activity and ATPase activity of p110alpha, indicating a change in molecular function.
Gene→Variant (gene-first): 5290:deletion of residues 1051-1068
Genes: 5290
Variants: deletion of residues 1051-1068
Our structure is for the WT p110alpha, but the kinase C-terminal tail more closely resembles those in the structures of the oncogenic mutant H1047R p110alpha/p85alpha-niSH2, than that in the WT apo p110alpha/p85alpha-iSH
[Paragraph-level] PMCID: PMC3378484 Section: RESULTS PassageIndex: 6
Evidence Type(s): Oncogenic, Functional
Justification: Oncogenic: The passage discusses the oncogenic mutant H1047R p110alpha, indicating that this variant is associated with tumor development or progression, particularly in the context of its structural characteristics compared to the wild-type. Functional: The passage describes how the H1047R variant affects the conformation of the C-terminal tail and its interactions, suggesting alterations in molecular or biochemical function related to the protein's structure.
Gene→Variant (gene-first): 5290:H1047R
Genes: 5290
Variants: H1047R
A crystal structure of mouse WT p110alpha in complex with human p85alpha niSH2 fragment and the p110beta/p110delta selective inhibitor PIK-108 has been determined and refined to 3.5 A (Rwork/Rfree=0.184/0.228) (acronyms
[Paragraph-level] PMCID: PMC3378484 Section: RESULTS PassageIndex: 3
Evidence Type(s): Functional
Justification: Functional: The passage discusses key conserved activation loop residues K942 and R949 and their importance in recognizing the substrate, indicating that these variants alter molecular function related to substrate binding.
Gene→Variant (gene-first): 5294:K942 5294:R949
Genes: 5294
Variants: K942 R949
This analysis reported a mutation in BRAF p.V600E c.1799T > A (8819 reads out of a total 16,712 sequence reads for an allele frequency of 52.77). After multidisciplinary discussion at our molecular tumour board, it was d
[Paragraph-level] PMCID: PMC4239128 Section: RESULTS PassageIndex: 2
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the potential vulnerability of the malignancy to BRAF inhibition, indicating a correlation between the BRAF p.V600E mutation and response to therapy with dabrafenib and trametinib. Oncogenic: The BRAF p.V600E mutation is implicated in the malignancy's development and progression, as it is associated with the treatment approach and the observed tumor response to therapy.
Gene→Variant (gene-first): 673:1799T > A 673:p.V600E
Genes: 673
Variants: 1799T > A p.V600E
Our data suggest that some clinically relevant D835 mutants retain sensitivity to type II inhibitors at clinically achievable drug concentrations and propose a molecular mechanism for differences in sensitivity for indiv
[Paragraph-level] PMCID: PMC4675689 Section: RESULTS PassageIndex: 8
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the sensitivity of D835 mutants to type II inhibitors, indicating a correlation with treatment response, which aligns with predictive evidence. Oncogenic: The mention of D835 mutations and their role in mediating resistance and sensitivity to FLT3 TKIs suggests that these somatic variants contribute to tumor development or progression.
Gene→Variant (gene-first): 2322:D835 2322:D835N/E
Genes: 2322
Variants: D835 D835N/E
Unlike the mutations discussed above, the models of the moderately resistant D835H mutation based each of the two template structures differ from each other. We assume the model based on the quizartinib template is more
[Paragraph-level] PMCID: PMC4675689 Section: RESULTS PassageIndex: 7
Evidence Type(s): Predictive, Functional
Justification: Predictive: The passage discusses the D835H mutation's resistance to type II inhibitors, indicating a correlation with treatment response and sensitivity to specific therapies. Functional: The passage describes how the D835H mutation alters the binding mode and hydrogen bond formation, indicating a change in molecular function related to inhibitor interaction.
Gene→Variant (gene-first): 2322:D835H
Genes: 2322
Variants: D835H
The most highly resistant mutants (D835Y/V/I/F) are large and bulky hydrophobic amino acid residues. In addition to an inability to hydrogen bond with S838, these large side chains are predicted to be sterically incompat
[Paragraph-level] PMCID: PMC4675689 Section: RESULTS PassageIndex: 6
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses how the D835Y/V variant alters molecular interactions and structural compatibility, indicating a change in biochemical function related to steric hindrance and hydrogen bonding. Oncogenic: The mention of "highly resistant mutants" suggests that the D835Y/V variant contributes to tumor development or progression by conferring resistance, which is characteristic of oncogenic behavior.
Gene→Variant (gene-first): 2322:D835Y/V
Genes: 2322
Variants: D835Y/V
The most sensitive mutants (D835E/N) are characterized by the predicted preservation of the hydrogen bond between D835 and S838 based on models utilizing both the apo and holo structures as templates. Side chains of the
[Paragraph-level] PMCID: PMC4675689 Section: RESULTS PassageIndex: 5
Evidence Type(s): Functional, Predictive
Justification: Functional: The passage discusses how the D835E/N mutations alter molecular interactions, specifically the formation of hydrogen bonds and the conservation of the alpha-helix structure, which affects inhibitor binding. Predictive: The passage indicates that the D835E/N variants are associated with sensitivity to type II inhibitors, suggesting a correlation with treatment response.
Gene→Variant (gene-first): 2322:D835 2322:D835E/N
Genes: 2322
Variants: D835 D835E/N
It is not straightforward to rationalize the effect of mutations near or in the short alpha-helix on the distant drug-binding active site. Nevertheless, it has been suggested that the short alpha-helix, which is part of
[Paragraph-level] PMCID: PMC4675689 Section: RESULTS PassageIndex: 4
Evidence Type(s): Predictive, Functional
Justification: Predictive: The passage discusses the correlation of D835 mutations with resistance to type II inhibitors, indicating a relationship between the variant and treatment response. Functional: The passage describes the impact of D835 mutations on the short alpha-helix and its potential effect on the drug-binding site, suggesting an alteration in molecular function related to drug interaction.
Gene→Variant (gene-first): 2322:D835
Genes: 2322
Variants: D835
Type II inhibitors bind to the conformation coupled to the DFG-out position of the kinase AL (residues 829-856 in FLT3). As previously noted, D835 is predicted to play a critical role in the stabilization of the DFG-out
[Paragraph-level] PMCID: PMC4675689 Section: RESULTS PassageIndex: 3
Evidence Type(s): Functional
Justification: Functional: The passage discusses how the D835 variant alters the molecular function of the kinase by stabilizing the DFG-out conformation and forming interactions that affect the structure of the alpha-helix.
Gene→Variant (gene-first): 2322:D835
Genes: 2322
Variants: D835
We profiled all D835 substitutions previously reported to cause FLT3 TKI resistance in patients, as well as D835 mutations occurring in patients as cataloged in the Sanger COSMIC database or the Cancer Genome Atlas. Inhi
[Paragraph-level] PMCID: PMC4675689 Section: RESULTS PassageIndex: 2
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses how various D835 substitutions correlate with resistance to FLT3 inhibitors, indicating their predictive value regarding treatment response. Oncogenic: The D835 mutations are reported to cause resistance in patients, suggesting that these somatic variants contribute to tumor development or progression.
Gene→Variant (gene-first): 2322:D835 2322:D835A/E 2322:D835H 2322:D835V/Y
Genes: 2322
Variants: D835 D835A/E D835H D835V/Y
In both patients with a clinical diagnosis of FAO (patients 2 and 3), targeted deep sequencing analysis led to the identification of a PIK3CA mutation in primary fibroblasts samples only. Specifically, a c.3140 A>G [p.H1
[Paragraph-level] PMCID: PMC4411002 Section: RESULTS PassageIndex: 16
Evidence Type(s): Diagnostic, Oncogenic
Justification: Diagnostic: The passage discusses the identification of PIK3CA mutations in patients with a clinical diagnosis of FAO, indicating that these variants are used to define or confirm the disease in these patients. Oncogenic: The PIK3CA mutations mentioned are somatic variants identified in primary fibroblasts, which suggests they contribute to tumor development or progression in the context of the patients' disease.
Gene→Variant (gene-first): 5294:3140 A>T 5290:c.3140 A>G 5290:c.3140 A>T 5290:p.H1047L 5290:p.H1047R
Genes: 5294 5290
Variants: 3140 A>T c.3140 A>G c.3140 A>T p.H1047L p.H1047R
This approach confirmed the presence of the c.241 G>A [p.E81K] mutation in the right and left leg biopsies of patient 1, with mutant allele frequencies of 9% and 21.5%, respectively (Fig 1d).
[Paragraph-level] PMCID: PMC4411002 Section: RESULTS PassageIndex: 15
Evidence Type(s): Diagnostic
Justification: Diagnostic: The passage confirms the presence of the c.241 G>A [p.E81K] mutation in the biopsies of a patient, indicating its role in defining or confirming the disease in that individual.
Gene→Variant (gene-first): 5290:c.241 G>A 5290:p.E81K
Genes: 5290
Variants: c.241 G>A p.E81K
Mutational analysis of PIK3CA exons and adjacent intronic regions was performed by Sanger sequencing methods on genomic DNA isolated from blood samples, tissue biopsies, and cultured dermal fibroblasts. No pathogenic var
[Paragraph-level] PMCID: PMC4411002 Section: RESULTS PassageIndex: 12
Evidence Type(s): Diagnostic, Oncogenic
Justification: Diagnostic: The passage discusses the identification of the c.241 G>A [p.E81K] mutation in a specific patient, indicating its association with the patient's condition and its absence in the patient's parents, which suggests its role in defining or confirming a disease. Oncogenic: The mention of the mutation being detected in various tissues of the patient, particularly in the context of a mutational analysis, implies its potential contribution to tumor development or progression.
Gene→Variant (gene-first): 5290:c.241 G>A 5290:p.E81K
Genes: 5290
Variants: c.241 G>A p.E81K
To identify molecules that could be pharmacologically targeted in NF1Mut melanomas, we first established 32 STCs from subcutaneous, lymph node, and brain metastases of 30 patients with melanoma (Fig. 1A; Supplementary Ta
[Paragraph-level] PMCID: PMC12221223 Section: RESULTS PassageIndex: 3
Evidence Type(s): Diagnostic, Oncogenic
Justification: Diagnostic: The passage discusses the identification of mutational profiles in melanoma, specifically mentioning that C>T transitions are characterized as cutaneous melanoma-defining features, which indicates a role in classifying or defining the disease. Oncogenic: The mention of C>T transitions as part of the mutational profile in melanoma suggests that these somatic variants contribute to tumor development or progression, particularly in the context of melanoma.
Gene→Variant (gene-first): 4763:C>T
Genes: 4763
Variants: C>T
Pilomyxoid astrocytomas are an aggressive subtype of astrocytoma, not graded by WHO, frequently located in hypothalamic/chiasmatic regions, affecting diencephalic structures, and characterized by shorter survival and hig
[Paragraph-level] PMCID: PMC8077124 Section: ABSTRACT PassageIndex: 10
Evidence Type(s): Oncogenic, Predictive
Justification: Oncogenic: The variant p.K656E is described as an activating and transforming mutation, indicating its role in tumor development or progression. Predictive: The variant p.V561M is mentioned as imparting resistance to FGFR inhibitors, suggesting its correlation with treatment response.
Gene→Variant (gene-first): 2260:p.K656E 2260:p.V561M
Genes: 2260
Variants: p.K656E p.V561M
Similar variant allele frequencies of FGFR1 p.K656E and FGFR1 p.V561M mutations in our patient's tumor suggest that these mutations may have occurred at similar time points. Use of FGFR inhibitors in addition to STAT3 or
[Paragraph-level] PMCID: PMC8077124 Section: ABSTRACT PassageIndex: 9
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the potential use of FGFR inhibitors in combination with other treatments, indicating a correlation with therapy response. Oncogenic: The mention of mutations in the context of a tumor suggests that the variants may contribute to tumor development or progression.
Gene→Variant (gene-first): 2260:p.K656E 2260:p.V561M
Genes: 2260
Variants: p.K656E p.V561M
We identified two somatic activating missense mutations affecting FGFR1, including FGFR1 p.K656E and FGFR1 p.V561M. While the former is a known hotspot mutation that is both activating and transforming, the latter has be
[Paragraph-level] PMCID: PMC8077124 Section: ABSTRACT PassageIndex: 7
Evidence Type(s): Oncogenic, Predictive
Justification: Oncogenic: The passage describes p.K656E as a known hotspot mutation that is activating and transforming, indicating its role in tumor development or progression. Predictive: The passage mentions that p.V561M is described as a gatekeeper mutation imparting resistance to FGFR inhibitors, which correlates with treatment response.
Gene→Variant (gene-first): 2260:p.K656E 2260:p.V561M
Genes: 2260
Variants: p.K656E p.V561M
Finally, patient UPN 2 was characterized by TKD D835Y mutation (43%) and a small ITD mutated clone (revealed only by UDS analysis, 0,4%) at diagnosis. After two months of conventional chemotherapy treatment (3+7 schedule
[Paragraph-level] PMCID: PMC4741605 Section: RESULTS PassageIndex: 20
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the response of the patient to chemotherapy treatment and how the presence of the D835Y mutation correlates with the patient's relapse, indicating its potential role in therapeutic decisions. Oncogenic: The D835Y mutation is described as a mutation that contributes to the tumor's behavior, particularly in the context of the patient's relapse and the increase in the mutated clone's percentage.
Gene→Variant (gene-first): 2322:D835Y
Genes: 2322
Variants: D835Y
Patient UPN 5 showed resistance to conventional induction chemotherapy (Cytarabine and Idarubicine). UDS analysis revealed a progressive expansion of the ITD+ clone over time (from 3,78% at diagnosis to 12,3% two months
[Paragraph-level] PMCID: PMC4741605 Section: RESULTS PassageIndex: 19
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the resistance of the D835Y variant to conventional induction chemotherapy and indicates that the treatment successfully inhibited the D835Y mutated clone, suggesting a correlation with treatment response. Oncogenic: The D835Y variant is mentioned in the context of tumor progression and its behavior in response to treatment, indicating its role in tumor development or progression.
Gene→Variant (gene-first): 2322:D835Y
Genes: 2322
Variants: D835Y
Patient UPN 4 received conventional induction chemotherapy and after an initial expansion of the FLT3 ITD+ clone, he achieved a complete morphological remission at the end of a "3+7" induction schedule. At molecular leve
[Paragraph-level] PMCID: PMC4741605 Section: RESULTS PassageIndex: 18
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage states that the mutations D839G and D835H are able to confer resistance to Sorafenib treatment, indicating a correlation between these variants and treatment response. Oncogenic: The presence of the D839G and D835H mutations is associated with the evolution of the FLT3 ITD+ clone and suggests a role in tumor development or progression, particularly in the context of acute myeloid leukemia (AML).
Gene→Variant (gene-first): 2322:D835H 2322:D839G
Genes: 2322
Variants: D835H D839G
Patient UPN 3 received best supportive therapy (BST). The ITD+ clone progressively increased (from 1,34% at diagnosis to 29,4% after 14 months of follow-up), along with the appearance of a minor ITD+ clone (0,6%) and two
[Paragraph-level] PMCID: PMC4741605 Section: RESULTS PassageIndex: 17
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the patient's response to the FLT3 inhibitor AC220-002, indicating that the presence of the D835Y and D839G variants may correlate with the patient's treatment response. Oncogenic: The D835Y and D839G variants are mentioned in the context of their abundance in the patient's sample, suggesting their potential role in tumor development or progression as part of the FLT3 mutation landscape.
Gene→Variant (gene-first): 2322:D835Y 2322:D839G
Genes: 2322
Variants: D835Y D839G
Since 2011, with the approval of crizotinib and subsequent approval of four additional targeted therapies, anaplastic lymphoma kinase (ALK) inhibitors have become important treatments for a subset of patients with lung c
[Paragraph-level] PMCID: PMC9398166 Section: ABSTRACT PassageIndex: 2
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses how the G1202R and L1196M mutations are major resistance mechanisms to ALK inhibitors, indicating that these variants correlate with resistance to specific therapies. Oncogenic: The G1202R and L1196M mutations are described as resistance mechanisms that contribute to tumor progression, particularly in the context of ALK inhibitors, suggesting their role in oncogenesis.
Gene→Variant (gene-first): 238:G1202R 238:L1196M
Genes: 238
Variants: G1202R L1196M
In order to assess if oncogenic BRAF signaling may induce venetoclax resistance, we overexpressed mutated BRAF (p.V600E) in a venetoclax-sensitive cell line OCI-LY19 (Fig. 3a). Exome sequencing of this cell line revealed
[Paragraph-level] PMCID: PMC5820258 Section: RESULTS PassageIndex: 16
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses how the BRAFV600E variant correlates with venetoclax resistance, indicating a relationship between the variant and treatment response. Oncogenic: The passage describes the overexpression of the mutated BRAF (p.V600E) in a cell line, which is associated with increased resistance to venetoclax, suggesting that this somatic variant contributes to tumor progression.
Gene→Variant (gene-first): 673:BRAFV600E 673:p.V600E 7157:p.W110*
Genes: 673 7157
Variants: BRAFV600E p.V600E p.W110*
Finally, case C586 showed a remarkable pattern of convergent evolution (Fig. 2d). We found two SF3B1 mutations (c.1996A > C; p.K666Q and c.1997A > C; p.K666T) affecting the same codon, but evolved in two independent clon
[Paragraph-level] PMCID: PMC5820258 Section: RESULTS PassageIndex: 14
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the SF3B1 mutations in the context of venetoclax exposure and resistance, indicating a correlation between these variants and treatment response. Oncogenic: The SF3B1 mutations are described as evolving during treatment and being selected for during venetoclax therapy, suggesting their role in tumor development or progression.
Gene→Variant (gene-first): 23451:c.1996A > C 23451:c.1997A > C 23451:p.K666Q 23451:p.K666T
Genes: 23451
Variants: c.1996A > C c.1997A > C p.K666Q p.K666T
Patient C548 showed a divergent evolutionary path of two branches (Fig. 2c). One branch (subclone C3 and C4) was selected during venetoclax therapy. This branch harbored a homozygous loss of CDKN2A/B, and mutations in BR
[Paragraph-level] PMCID: PMC5820258 Section: RESULTS PassageIndex: 13
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the selection of specific mutations (including p.K601E and p.Q547fs) during venetoclax therapy, indicating a correlation with treatment response. Oncogenic: The mutations p.K601E and p.S321fs are described as contributing to tumor development, as they are retained in the clonal evolution of the cancer during relapse.
Gene→Variant (gene-first): 673:p.K601E 330:p.Q547fs 58508:p.S321fs
Genes: 673 330 58508
Variants: p.K601E p.Q547fs p.S321fs
To gain insight into the clonal evolution towards therapy resistance, we inferred subclonal populations and reconstructed phylogenetic trees (see Methods). Intriguingly, we observed a wide spectrum of evolutionary dynami
[Paragraph-level] PMCID: PMC5820258 Section: RESULTS PassageIndex: 12
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the involvement of BTG1 mutations (p.E46K and p.Q36H) in the resistance to venetoclax treatment, indicating a correlation between these variants and treatment response. Oncogenic: The passage describes the BTG1 mutations as being involved in the clonal evolution towards therapy resistance, suggesting that these somatic variants contribute to tumor development or progression.
Gene→Variant (gene-first): 7157:p.E46K 694:p.Q36H
Genes: 7157 694
Variants: p.E46K p.Q36H
Recurrent genomic changes that evolved during venetoclax treatment were homozygous deletions affecting CDKN2A/B in three patients (C548, C577, C586) and BTG1 missense mutations in two cases (C577: p.Q36H; C789: p.E46K).
[Paragraph-level] PMCID: PMC5820258 Section: RESULTS PassageIndex: 10
Evidence Type(s): Oncogenic, Functional
Justification: Oncogenic: The passage discusses how damaging mutations in BTG1, including the p.Q36H and p.E46K variants, may provide a survival advantage to CLL cells under targeted BCL2-inhibition, indicating their contribution to tumor development or progression. Functional: The passage mentions that BTG1 has been shown to counteract cell proliferation, suggesting that the mutations may alter its molecular or biochemical function.
Gene→Variant (gene-first): 7157:p.E46K 694:p.Q36H
Genes: 7157 694
Variants: p.E46K p.Q36H