EPHB4-V871I increases the expression of some target genes and enhance the phosphorylation of ERK1-2 pathway
[Paragraph-level] PMCID: PMC7294133 Section: RESULTS PassageIndex: 14
Evidence Type(s): Functional
Justification: Functional: The variant V871I alters molecular function by increasing the expression of target genes and enhancing the phosphorylation of the ERK1-2 pathway.
Gene→Variant (gene-first): 2050:V871I
Genes: 2050
Variants: V871I
We further analysed the anchorage-independent growth of EPHB4-MUT by colony formation assay in soft agar. EPHB4-V871I showed an increased number of colonies compared with WT and EV in both cell lines (Figure 4B).
[Paragraph-level] PMCID: PMC7294133 Section: RESULTS PassageIndex: 13
Evidence Type(s): Oncogenic, Functional
Justification: Oncogenic: The variant EPHB4-V871I is associated with increased anchorage-independent growth, indicating its contribution to tumor development or progression as demonstrated by the colony formation assay. Functional: The passage describes the effect of the EPHB4-V871I variant on cellular behavior, specifically its impact on colony formation, which suggests an alteration in molecular or biochemical function.
Gene→Variant (gene-first): 2050:V871I
Genes: 2050
Variants: V871I
We further analysed the migration properties of EPHB4 mutant clone by two-dimensional migration experiments. EPHB4-V871I showed an increased number of migrating cells compared with EV and EPHB4-WT in both cell lines (Fig
[Paragraph-level] PMCID: PMC7294133 Section: RESULTS PassageIndex: 12
Evidence Type(s): Functional
Justification: Functional: The passage discusses how the EPHB4-V871I variant alters the migration properties of cells, indicating a change in molecular function related to cell behavior.
Gene→Variant (gene-first): 2050:V871I
Genes: 2050
Variants: V871I
The migration potential was firstly assayed by wound-healing experiments demonstrating increased migration properties of EPHB4-V871I compared with both EV and EPHB4-WT in both cell lines (Figure 3C). Indeed, the percenta
[Paragraph-level] PMCID: PMC7294133 Section: RESULTS PassageIndex: 11
Evidence Type(s): Functional
Justification: Functional: The passage discusses how the EPHB4-V871I variant alters the migration properties of cells, indicating a change in molecular function related to cell behavior.
Gene→Variant (gene-first): 2050:V871I
Genes: 2050
Variants: V871I
Due to EPHB4 involvement in tumour angiogenesis, growth and metastasis, 21 we speculated on its potential regulation of cellular proliferation, cell migration and anchorage-independent growth in vitro. The proliferation
[Paragraph-level] PMCID: PMC7294133 Section: RESULTS PassageIndex: 10
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses how the EPHB4-V871I variant alters the proliferation rate of cells, indicating a change in molecular or biochemical function. Oncogenic: The increased proliferation rate associated with the EPHB4-V871I variant suggests its contribution to tumor development or progression, as it is linked to cellular behaviors relevant to cancer.
Gene→Variant (gene-first): 2050:V871I
Genes: 2050
Variants: V871I
EPHB4-V871I affects proliferation and migration of NB cell lines
[Paragraph-level] PMCID: PMC7294133 Section: RESULTS PassageIndex: 9
Evidence Type(s): Functional
Justification: Functional: The passage indicates that EPHB4-V871I alters the proliferation and migration of neuroblastoma (NB) cell lines, suggesting a change in molecular or biochemical function.
Gene→Variant (gene-first): 2050:V871I
Genes: 2050
Variants: V871I
In order to select the cell lines to perform the functional characterization of EPHB4-V871I variant, we firstly analysed the expression of EPHB4 in several NB cell lines. We divided our cell lines based on MYCN amplified
[Paragraph-level] PMCID: PMC7294133 Section: RESULTS PassageIndex: 8
Evidence Type(s): Functional
Justification: Functional: The passage discusses the functional characterization of the EPHB4-V871I variant, specifically evaluating its expression and confirming that the mutation does not impair EPHB4 expression at the mRNA and protein level.
Gene→Variant (gene-first): 2050:V871I
Genes: 2050
Variants: V871I
The screening of kinome regions in NB cell lines resulted in 11 filtered mutations in eight genes. Here, we detected four additional ALK mutations. Of these, three were F1174L changes, and the other was the R1275Q change
[Paragraph-level] PMCID: PMC7294133 Section: RESULTS PassageIndex: 5
Evidence Type(s): None
Justification: Not enough information in this passage.
Gene→Variant (gene-first): 238:F1174L 2260:N457K 238:R1275Q
Genes: 238 2260
Variants: F1174L N457K R1275Q
Interestingly, we found two mutations in EPHB4 (V871I) and in EphB6 (A417S) genes, both involved in axon guidance pathway. The variant V871I in the kinase domain of EPHB4 showed a high pathogenic score (Figure 1A and Tab
[Paragraph-level] PMCID: PMC7294133 Section: RESULTS PassageIndex: 4
Evidence Type(s): Oncogenic, Functional
Justification: Oncogenic: The passage discusses mutations in EPHB4 and EphB6 genes, indicating that the variant V871I is associated with a high pathogenic score, suggesting its contribution to tumor development or progression. Functional: The mention of the variant V871I being located in the kinase domain of EPHB4 implies a potential alteration in molecular or biochemical function related to its role in the axon guidance pathway.
Gene→Variant (gene-first): 4613:A417S 2050:V871I
Genes: 4613 2050
Variants: A417S V871I
We performed targeted sequencing of TK domains on a total of 45 NB normal-primary tumour matched pairs and 9 NB cell lines. All tumour samples were high-risk patients according to the COG Risk Group Classification System
[Paragraph-level] PMCID: PMC7294133 Section: RESULTS PassageIndex: 3
Evidence Type(s): Oncogenic
Justification: Oncogenic: The passage indicates that the variant F1174L is a somatic mutation found in the ALK gene, which is associated with neuroblastoma (NB), suggesting its contribution to tumor development or progression.
Gene→Variant (gene-first): 238:F1174L
Genes: 238
Variants: F1174L
Kinome sequencing and identification of EPHB4-V871I mutation in NB patients
[Paragraph-level] PMCID: PMC7294133 Section: RESULTS PassageIndex: 2
Evidence Type(s): None
Justification: Not enough information in this passage.
Gene→Variant (gene-first): 2050:V871I
Genes: 2050
Variants: V871I
Consistent with our hierarchical clustering analysis, introduction of the R164Q mutation led to relatively few changes in gene expression or showed reduced pathway activation compared with the other mutants studied. Howe
[Paragraph-level] PMCID: PMC2837563 Section: RESULTS PassageIndex: 15
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses how the introduction of the R164Q mutation led to changes in gene expression and pathway activation, indicating that the variant alters molecular function. Oncogenic: The mention of the A146T, K117N, G13D, and Q61H mutations clustering together and influencing gene expression suggests that these somatic variants contribute to tumor development or progression.
Gene→Variant (gene-first): 3845:A146T 3845:G13D 3845:K117N 3845:L19F 3845:Q61H 3845:R164Q
Genes: 3845
Variants: A146T G13D K117N L19F Q61H R164Q
To further compare and contrast the phenotypes associated with each of the K-Ras mutants, transcription-profiling experiments were carried out as described in Materials and Methods. Hierarchical clustering analysis revea
[Paragraph-level] PMCID: PMC2837563 Section: RESULTS PassageIndex: 13
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses transcription-profiling experiments and Ras GTPase assay data, indicating that the variants alter molecular or biochemical function, particularly in relation to their clustering and phenotypic characteristics. Oncogenic: The mention of the variants being associated with distinct phenotypes and their clustering suggests that these somatic mutations contribute to tumor development or progression.
Gene→Variant (gene-first): 3845:A146T 3845:G12C 3845:G12D 3845:G12V 3845:G13D 3845:K117N 3845:L19F 3845:R164Q
Genes: 3845
Variants: A146T G12C G12D G12V G13D K117N L19F R164Q
To assess which K-Ras mutations were in the active GTP-bound conformation, a Raf-1 binding assay was carried out as described in Materials and Methods. Raf-1 selectively binds GTP-bound Ras (rather than the inactive GDP-
[Paragraph-level] PMCID: PMC2837563 Section: RESULTS PassageIndex: 11
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses how specific K-Ras mutations (G12V, L19F, K117N, A146T) are in the active GTP-bound conformation, indicating that these variants alter the molecular function of the K-Ras protein. Oncogenic: The mention of K-Ras mutations being in the active GTP-bound conformation suggests that these somatic variants contribute to tumor development or progression, as they are associated with active signaling pathways in cancer.
Gene→Variant (gene-first): 3845:A146T 3845:G12V 3845:K117N 3845:L19F 3845:R164Q
Genes: 3845
Variants: A146T G12V K117N L19F R164Q
Phenotypes associated with the various K-Ras mutations have previously not been systematically evaluated. To compare the transformation potential of the K-Ras mutants, therefore, NIH3T3 cells were transiently transfected
[Paragraph-level] PMCID: PMC2837563 Section: RESULTS PassageIndex: 9
Evidence Type(s): Oncogenic, Functional
Justification: Oncogenic: The passage discusses the transformation potential of various K-Ras mutations, indicating that these mutations contribute to tumor development as evidenced by the formation of foci in NIH3T3 cells after transfection. Functional: The study evaluates the molecular function of K-Ras mutations by assessing their ability to transform cells, which involves alterations in biochemical activity as demonstrated through focus formation assays.
Gene→Variant (gene-first): 3845:A146T 3845:G12D 3845:G12V 3845:G13D 3845:K117N 3845:L19F 3845:Q61H 3845:R164Q
Genes: 3845
Variants: A146T G12D G12V G13D K117N L19F Q61H R164Q
To identify additional K-Ras mutations, and to establish the relative frequencies of individual K-Ras mutations in human colorectal tumours, we used WAVE analysis followed by direct sequencing to screen the same tumour s
[Paragraph-level] PMCID: PMC2837563 Section: RESULTS PassageIndex: 4
Evidence Type(s): Diagnostic, Oncogenic, Functional
Justification: Diagnostic: The passage discusses the identification and relative frequencies of K-Ras mutations in human colorectal tumors, indicating their association with the disease. Oncogenic: The mention of K-Ras mutations, including the V600E mutation, suggests their contribution to tumor development or progression, as they are associated with increased mutation frequency in the Ras pathway. Functional: The passage notes the predicted localization of each mutation in the functional domains of the K-Ras protein, indicating an alteration in molecular function.
Gene→Variant (gene-first): 3845:A to C 3845:Ala to Thr 3845:Arg to Gln 3845:C to T 3845:G to A 3845:Lys to Asn 673:V600E 3845:aspartic acid residue at codon 173
Genes: 3845 673
Variants: A to C Ala to Thr Arg to Gln C to T G to A Lys to Asn V600E aspartic acid residue at codon 173
We have previously described K-Ras mutations at codons 12, 13 and 61 in a series of 106 unselected colorectal tumours. Our K-Ras mutation analysis was performed by direct sequencing of K-Ras exon 1 (codons 12 and 13) and
[Paragraph-level] PMCID: PMC2837563 Section: RESULTS PassageIndex: 3
Evidence Type(s): Diagnostic, Oncogenic
Justification: Diagnostic: The passage discusses the detection of specific mutations in colorectal tumors, indicating their association with the disease, which supports their use in defining or classifying the disease. Oncogenic: The mention of mutations at codon 19 (G57T, Leu19Phe) and in B-Raf (V600E) suggests that these somatic variants may contribute to tumor development, as they are found in tumor samples.
Gene→Variant (gene-first): 673:G57T 3845:Leu19Phe 673:V600E
Genes: 673 3845
Variants: G57T Leu19Phe V600E
To determine if the synergy observed in vitro for PARPi-resistant cells translated to in vivo efficacy, SRA737 and PARPi combination therapy was tested in five HGSOC PDX models. Two HR competent CCNE1 amplified HGSOC PDX
[Paragraph-level] PMCID: PMC11253285 Section: RESULTS PassageIndex: 18
Evidence Type(s): Predictive, Prognostic
Justification: Predictive: The passage discusses the response to therapy involving SRA737 and PARP inhibitors (PARPi), indicating a correlation with treatment response in specific PDX models. Prognostic: The mention of a trending increase in survival with combination therapy compared to monotherapy suggests a correlation with disease outcome, although it did not reach statistical significance.
Gene→Variant (gene-first): 142:S4D
Genes: 142
Variants: S4D
PARPi-resistant JHOS4 PR (BRCA1MUT), PEO1 PR (BRCA2MUT), FUOV1, and OVCAR3 (CCNE1amp) cells were further tested for the mechanism by which SRA737 and PARPi synergistically inhibit tumor cell growth. Parental PEO1 and JHO
[Paragraph-level] PMCID: PMC11253285 Section: RESULTS PassageIndex: 15
Evidence Type(s): Oncogenic, Functional
Justification: Oncogenic: The passage discusses the mechanism by which SRA737 and PARPi synergistically inhibit tumor cell growth, indicating that the variant S3C is involved in tumor development or progression through its effects on cell lines with specific mutations. Functional: The passage describes how exposure to SRA737 results in specific phosphorylation changes in CHK1 and other proteins, indicating that the variant alters molecular or biochemical function related to tumor cell growth.
Gene→Variant (gene-first): 1111:S3C
Genes: 1111
Variants: S3C
To characterize the AR mechanism through RET fusions in EGFR-mutated NSCLC patients and their survival outcomes, we compared the PFS among patients treated with different EGFR-TKI regimens. However, no significant differ
[Paragraph-level] PMCID: PMC9441062 Section: RESULTS PassageIndex: 15
Evidence Type(s): Diagnostic, Prognostic
Justification: Diagnostic: The passage mentions that patients with L858R mutations were included in a refined cohort, indicating that this variant is used to classify or define a specific group of patients with EGFR mutations in NSCLC. Prognostic: The passage discusses the progression-free survival (PFS) of patients with specific mutations, including L858R, suggesting that this variant correlates with disease outcome independent of therapy.
Gene→Variant (gene-first): 1956:L858R
Genes: 1956
Variants: L858R
Despite their rarity, it is clear from previous studies that RTK fusions, such as RET rearrangements, are actionable resistance mechanisms to EGFR-TKIs. We aim to increase awareness of this emerging paradigm by comprehen
[Paragraph-level] PMCID: PMC9441062 Section: RESULTS PassageIndex: 14
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses how the variants T790M, C797S/G, and L718V/Q are associated with resistance mechanisms to EGFR-TKIs, indicating their role in treatment response. Oncogenic: The variants mentioned are described as second-site mutations that contribute to resistance in the context of tumor development and progression in NSCLC.
Gene→Variant (gene-first): 1956:C797S/G 1956:L718V/Q 1956:T790M
Genes: 1956
Variants: C797S/G L718V/Q T790M
In the baseline cohort, 58.9% of patients were under 60 years (58.9% vs. 41.1%, P < 0.001), and the proportion of females was significantly higher than males (55.3% vs. 44.7%, P = 0.038, Table 1). Of the 71 patients with
[Paragraph-level] PMCID: PMC9441062 Section: RESULTS PassageIndex: 4
Evidence Type(s): Diagnostic, Oncogenic
Justification: Diagnostic: The passage states that all 71 patients harbored baseline EGFR mutations, including specific variants, indicating their role in defining the patient cohort and confirming the presence of a disease subtype (NSCLC). Oncogenic: The mention of EGFR mutations, including G719C, L858R, and S768I, suggests that these somatic variants contribute to tumor development or progression in the context of non-small cell lung cancer (NSCLC).
Gene→Variant (gene-first): 1956:G719C 1956:L858R 1956:S768I
Genes: 1956
Variants: G719C L858R S768I
Among 550 patients included in cfDNA analysis, median PFS in everolimus vs placebo arms was similar in patients with tumours that had wild-type or mutant PIK3CA (hazard ratio (HR), 0.43 and 0.37, respectively). Everolimu
[Paragraph-level] PMCID: PMC5355930 Section: ABSTRACT PassageIndex: 6
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the correlation between PIK3CA mutations (H1047R, E545K, E542K) and the response to the therapy everolimus, indicating that these variants are associated with treatment outcomes. Oncogenic: The mention of PIK3CA mutations in the context of tumor analysis suggests that these somatic variants contribute to tumor development or progression, particularly in relation to their response to therapy.
Gene→Variant (gene-first): 5290:E542K 5290:E545K 5290:H1047R
Genes: 5290
Variants: E542K E545K H1047R
PIK3CA H1047R, E545K, and E542K mutations in plasma-derived cfDNA were analysed by droplet digital PCR (ddPCR). Median PFS was estimated for patient subgroups defined by PIK3CA mutations in each treatment arm.
[Paragraph-level] PMCID: PMC5355930 Section: ABSTRACT PassageIndex: 4
Evidence Type(s): Diagnostic, Prognostic
Justification: Diagnostic: The passage discusses the analysis of PIK3CA mutations to define patient subgroups, indicating that these variants are used to classify or associate with a disease or subtype. Prognostic: The mention of estimating median progression-free survival (PFS) for patient subgroups defined by PIK3CA mutations suggests a correlation with disease outcome independent of therapy.
Gene→Variant (gene-first): 5290:E542K 5290:E545K 5290:H1047R
Genes: 5290
Variants: E542K E545K H1047R
In the placebo arm, patients with E545K/E542K mutation had shorter PFS and overall survival than those with wild-type PIK3CA (Supplementary Table 2), suggesting that PIK3CA mutations in the helical domain might play a ro
[Paragraph-level] PMCID: PMC5355930 Section: RESULTS PassageIndex: 9
Evidence Type(s): Predictive, Prognostic
Justification: Predictive: The passage suggests that patients with E545K/E542K mutations had shorter progression-free survival (PFS) and overall survival, indicating a potential role of these mutations in resistance to hormone therapy. Prognostic: The mention of shorter PFS and overall survival in patients with the E545K/E542K mutations indicates a correlation with disease outcome independent of therapy.
Gene→Variant (gene-first): 5290:E542K 5290:E545K
Genes: 5290
Variants: E542K E545K
To examine the role of domain-specific mutations in PIK3CA on everolimus efficacy, patients were categorised by mutation site, H1047R in the catalytic domain, and E545K and E542K in the helical domain. Everolimus prolong
[Paragraph-level] PMCID: PMC5355930 Section: RESULTS PassageIndex: 8
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the correlation between PIK3CA mutations (H1047R, E545K, E542K) and the efficacy of everolimus, indicating that these variants are associated with prolonged progression-free survival (PFS) in patients treated with this therapy. Oncogenic: The mention of PIK3CA mutations in the context of their role in tumor development and the efficacy of a cancer treatment suggests that these somatic variants contribute to tumor progression.
Gene→Variant (gene-first): 5290:E542K 5290:E545K 5290:H1047R
Genes: 5290
Variants: E542K E545K H1047R
Of the 724 patients in BOLERO-2, 550 patients (76%) underwent PIK3CA cfDNA analysis. The baseline characteristics and clinical outcomes were similar between the cfDNA and overall population (Supplementary Table 1). PIK3C
[Paragraph-level] PMCID: PMC5355930 Section: RESULTS PassageIndex: 3
Evidence Type(s): Diagnostic, Predictive
Justification: Diagnostic: The passage discusses the prevalence of PIK3CA mutations, including specific variants, in a patient population, indicating their association with the disease context. Predictive: The mention of higher prevalence of PIK3CA mutations in the everolimus arm compared to the placebo arm suggests a correlation with treatment response, indicating predictive value.
Gene→Variant (gene-first): 5290:E542K 5290:E545K 5290:H1047R
Genes: 5290
Variants: E542K E545K H1047R
We next selected two gastroesophageal PDX models with HER2 overexpression (IHC 3+) and ERBB2 amplification. We tested PDX.003.230, a model that is HER2 3+ and ERBB2 amplified. This model was also noted to have an ERBB2 T
[Paragraph-level] PMCID: PMC10618648 Section: RESULTS PassageIndex: 20
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The T733I mutation is associated with resistance to lapatinib and sensitivity to adavosertib, indicating its role in predicting treatment response. Oncogenic: The T733I mutation is described as weakly transforming, suggesting it contributes to tumor development or progression in the context of the PDX model.
Gene→Variant (gene-first): 2064:T733I
Genes: 2064
Variants: T733I
We first assessed the combination of T-DXd with adavosertib in PDXs with low HER2 expression. PDX.003.204 (HER2 2+ IHC, CCNE1 amplified) demonstrated modest tumor growth inhibition with T-DXd monotherapy as shown by a re
[Paragraph-level] PMCID: PMC10618648 Section: RESULTS PassageIndex: 16
Evidence Type(s): Oncogenic, Functional
Justification: Oncogenic: The passage indicates that ERBB2 mutations (V777L, G778A) were identified in the tyrosine kinase domain, suggesting that these somatic variants contribute to tumor development or progression. Functional: The mention of ERBB2 mutations in the tyrosine kinase domain implies that these variants may alter molecular or biochemical function, which is characteristic of functional evidence.
Gene→Variant (gene-first): 2064:G778A 2064:V777L
Genes: 2064
Variants: G778A V777L
Apoptosis was assessed by annexin V staining to determine the effects of adavosertib in combination with DXd or T-DXd in MKN7 cells. Although both DXd and T-DXd were capable of inducing apoptosis (5-20%), combination of
[Paragraph-level] PMCID: PMC10618648 Section: RESULTS PassageIndex: 11
Evidence Type(s): None
Justification: Not enough information in this passage.
Gene→Variant (gene-first): 2064:E in 72
Genes: 2064
Variants: E in 72
Across the study cohort of 151 tumors (Figs. 2-4; Supplementary Table 4), KIAA1549-BRAF fusions were detected in PAs, two pilomyxoid astrocytomas (PMAs), and a single brainstem ganglioglioma, and were present in 59%, 90%
[Paragraph-level] PMCID: PMC3727232 Section: RESULTS PassageIndex: 11
Evidence Type(s): Diagnostic, Oncogenic
Justification: Diagnostic: The passage discusses the detection of BRAF:p.V600E mutations in various tumor types, indicating its association with specific tumor classifications, which supports its use as a biomarker for diagnosis. Oncogenic: The H3F3A:p.K27M mutation is described as being present in specific tumor types, indicating its contribution to tumor development or progression.
Gene→Variant (gene-first): 3021:p.K27M 673:p.V600E
Genes: 3021 673
Variants: p.K27M p.V600E
Only four of 39 tumors (10%) in the WGS series lacked a MYB/MYBL1 rearrangement, FGFR1 alteration, or aberration of a gene in the NF1/RAS/RAF pathway. One of these, SJLGG034, was an oligodendroglioma from a patient aged
[Paragraph-level] PMCID: PMC3727232 Section: RESULTS PassageIndex: 6
Evidence Type(s): None
Justification: Not enough information in this passage.
Gene→Variant (gene-first): 1106:p.D1722V 1029:p.P101L 3417:p.R132H 23152:p.S726R 23152:p.V676fs
Genes: 1106 1029 3417 23152
Variants: p.D1722V p.P101L p.R132H p.S726R p.V676fs
Remarkably, the median number of non-silent somatic sequence mutations and SVs per tumor in the WGS (discovery) series was one, suggesting that few genetic alterations are required for oncogenesis (Fig. 1; Supplementary
[Paragraph-level] PMCID: PMC3727232 Section: RESULTS PassageIndex: 5
Evidence Type(s): Oncogenic, Diagnostic
Justification: Oncogenic: The passage discusses the H3F3A:p.K27M mutation and BRAF:p.V600E mutation as recurrent abnormalities in specific tumor types, indicating their contribution to tumor development or progression. Diagnostic: The mention of BRAF:p.V600E mutations being frequent in pleomorphic xanthoastrocytomas suggests its use in defining or classifying this subtype of tumor.
Gene→Variant (gene-first): 3021:p.K27M 673:p.V600E
Genes: 3021 673
Variants: p.K27M p.V600E
We detected somatic mutations in 10 of 16 specimens (63%). Eight had KRAS mutations [G12D (n = 5), G12V (n = 3)] and two had BRAF mutations [V600E (n = 1), Q636X (n = 1)]. We found no difference in age, sex, presenting s
[Paragraph-level] PMCID: PMC6938308 Section: ABSTRACT PassageIndex: 6
Evidence Type(s): Oncogenic, Diagnostic
Justification: Oncogenic: The passage discusses somatic mutations in KRAS and BRAF, indicating that these variants contribute to tumor development as they are detected in specimens from patients with AVM. Diagnostic: The presence of specific mutations (G12D, G12V, V600E, Q636X) is used to classify and confirm the mutation status of patients, which is relevant for understanding their disease.
Gene→Variant (gene-first): 3845:G12D 3845:G12V 673:Q636X 673:V600E
Genes: 3845 673
Variants: G12D G12V Q636X V600E
We next examined how these function scores varied in apparently healthy populations (Figures 3C and 3D). The gnomAD database lists 744 of the scored MSH2 missense variants, nearly all rare (742/744 with minor allele freq
[Paragraph-level] PMCID: PMC7820803 Section: RESULTS PassageIndex: 13
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses how the variant p.Ala636Pro scored as deleterious in an assay, indicating that it alters molecular or biochemical function. Oncogenic: The context of the passage suggests that the variant is associated with bi-allelic MMR loss, which contributes to tumor development in pediatric-onset cancer syndromes, indicating its role in oncogenesis.
Gene→Variant (gene-first): 4436:p.Ala636Pro
Genes: 4436
Variants: p.Ala636Pro
Each MSH2 mutant cell pool was then selected en masse for MMR deficiency. To allow comparison across pools, each was spiked with barcoded control cells (KO+WT: 10% of cells; KO+p.Ala636Pro: 0.5%). Pools were then grown u
[Paragraph-level] PMCID: PMC7820803 Section: RESULTS PassageIndex: 7
Evidence Type(s): Oncogenic, Functional
Justification: Oncogenic: The passage discusses the selection of MSH2 mutant cells, specifically the p.Ala636Pro variant, in the context of MMR deficiency, indicating that this somatic variant contributes to tumor development or progression. Functional: The passage describes the behavior of the p.Ala636Pro variant in a selective environment, suggesting that it alters the molecular function of the MSH2 protein, as evidenced by the enrichment of these cells under selective conditions.
Gene→Variant (gene-first): 4436:p.Ala636Pro
Genes: 4436
Variants: p.Ala636Pro
As a readout for MSH2 function, we leveraged selection with the purine analog 6-thioguanine (6-TG). Incorporation of 6-TG is selectively toxic to MMR-proficient cells, as it creates lesions that the MMR machinery recogni
[Paragraph-level] PMCID: PMC7820803 Section: RESULTS PassageIndex: 4
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses how the p.Ala636Pro variant affects the sensitivity to 6-thioguanine, indicating that it alters the molecular function of MSH2 in the context of mismatch repair. Oncogenic: The passage implies that the p.Ala636Pro variant is pathogenic and contributes to the resistance of cells to 6-thioguanine, suggesting a role in tumor development or progression.
Gene→Variant (gene-first): 4436:p.Ala636Pro
Genes: 4436
Variants: p.Ala636Pro
We established a human cell system to model MSH2 variant function using the near-haploid, mismatch repair proficient cell line HAP1 (Figures 1A and 1C). First, to disrupt MMR, we derived clonal MSH2 knockout cells bearin
[Paragraph-level] PMCID: PMC7820803 Section: RESULTS PassageIndex: 3
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses how the p.Ala636Pro variant affects the expression levels of MSH2 protein, indicating that it alters molecular function by being barely detectable compared to wild-type MSH2, which demonstrates its destabilizing effect. Oncogenic: The passage describes the use of the p.Ala636Pro variant in a model to disrupt mismatch repair (MMR), suggesting that this somatic variant contributes to tumor development or progression by affecting MSH2 function.
Gene→Variant (gene-first): 4436:p.Ala636Pro
Genes: 4436
Variants: p.Ala636Pro
We defined mutations in druggable tyrosine kinase domains including in ERBB2 (a V777L and a 755-759 LRENT in frame deletion homologous to gefitinib-activating EGFR mutations in lung cancer ), as well as in DDR1 (A829V, R
[Paragraph-level] PMCID: PMC3383766 Section: RESULTS PassageIndex: 21
Evidence Type(s): Diagnostic, Oncogenic
Justification: Diagnostic: The passage discusses mutations in specific genes that are associated with druggable tyrosine kinase domains, indicating their relevance in defining or classifying disease subtypes. Oncogenic: The mention of mutations in tyrosine kinase domains suggests that these variants may contribute to tumor development or progression, particularly in the context of cancer-related mutations.
Gene→Variant (gene-first): 780:A829V 207:C77F 405:D735H 3084:E583D 2048:E924K 5156:M875L 780:R611C 208:S11F 3169:S375F 2064:V777L
Genes: 780 207 405 3084 2048 5156 208 3169 2064
Variants: A829V C77F D735H E583D E924K M875L R611C S11F S375F V777L
To study clinical correlations, mutation recurrence screening was conducted on an additional 240 cases (Supplementary Table 8 and Supplementary Fig. 1). By combining WGS, exome, and recurrence screening data, we determin
[Paragraph-level] PMCID: PMC3383766 Section: RESULTS PassageIndex: 10
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage indicates that the M294K mutation in GATA3 is one of several mutations that include truncation events, suggesting a role in functional inactivation of the protein. Oncogenic: The mention of M294K as a recurrent mutation in tumors suggests that it may contribute to tumor development or progression, particularly in the context of GATA3 being identified as a tumor suppressor.
Gene→Variant (gene-first): 2625:M294K
Genes: 2625
Variants: M294K
We also identified three SMGs (LDLRAP1, AGTR2, and STMN2), not previously implicated in cancer. A missense and a nonsense mutation were observed in LDLRAP1, a gene associated with familial hypercholesterolemia. AGTR2, an
[Paragraph-level] PMCID: PMC3383766 Section: RESULTS PassageIndex: 8
Evidence Type(s): Diagnostic, Oncogenic
Justification: Diagnostic: The passage mentions that AGTR2 harbored two missense mutations (V184I and R251H) and describes AGTR2 as a gene associated with familial hypercholesterolemia, indicating its role in defining or classifying a disease. Oncogenic: The passage discusses mutations in AGTR2 and their potential involvement in angiotensin signaling and tissue fibrosis, which are relevant to tumor development or progression, suggesting a role in oncogenesis.
Gene→Variant (gene-first): 186:R251H 186:V184I
Genes: 186
Variants: R251H V184I
Thirteen mutations (3 nonsense, 6 frame-shift indels, 2 in-frame deletions and 2 missense) were identified in MAP3K1 (Table 1 and Fig. 2), a serine/threonine kinase that activates the ERK and JNK kinase pathways through
[Paragraph-level] PMCID: PMC3383766 Section: RESULTS PassageIndex: 7
Evidence Type(s): Oncogenic, Functional
Justification: Oncogenic: The passage discusses mutations in RUNX1, which is implicated in the M2 subtype of AML, indicating that these somatic variants contribute to tumor development or progression. Functional: The passage mentions that mutations in RUNX1 affect its role as a transcription factor, which suggests that these variants alter molecular or biochemical function.
Gene→Variant (gene-first): 9757:G168E 23451:K666Q 23451:K700E 4216:N104S 861:R166Q 1588:R169K 51742:S184L
Genes: 9757 23451 4216 861 1588 51742
Variants: G168E K666Q K700E N104S R166Q R169K S184L
Somatic missense mutations in PIK3CA, which encodes the p110alpha catalytic subunit of phosphoinositide 3-kinases (PI3Ks), occur frequently in human cancers. Activating mutations spread across multiple domains, some of w
[Paragraph-level] PMCID: PMC3378484 Section: ABSTRACT PassageIndex: 1
Evidence Type(s): Oncogenic, Functional
Justification: Oncogenic: The passage discusses somatic missense mutations in PIK3CA that contribute to increased kinase activities and lipid binding, indicating their role in tumor development or progression. Functional: The passage describes how specific mutations alter the molecular function of the p110alpha protein, including increased basal activity and lipid binding, which are indicative of changes in biochemical function.
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
Candidate canonical RBDs mainly include the RNA recognition motif (RRM), zinc fingers (ZF), tryptophan-aspartic acid 40 (WD40), K homology (KH) domain, double-stranded RNA-binding motif (DSRM), TUDOR domain, cold shock d
[Paragraph-level] PMCID: PMC7226056 Section: RESULTS PassageIndex: 7
Evidence Type(s): None
Justification: Not enough information in this passage.
Gene→Variant (gene-first): 7015:tryptophan-aspartic acid 40
Genes: 7015
Variants: tryptophan-aspartic acid 40
Next, we analyzed the expression patterns of RBPs in different types of glioma patients and compared their abundance in expression levels. In our studies, a global analysis of the expression of the mRNA levels of RBPs re
[Paragraph-level] PMCID: PMC7226056 Section: RESULTS PassageIndex: 5
Evidence Type(s): Diagnostic, Oncogenic, Prognostic
Justification: Diagnostic: The passage discusses the reclassification of glioma patients into different types based on expression levels and molecular alterations, indicating that these variants are used to define or classify the disease. Oncogenic: The mention of TERT mutation in gliomas suggests that this somatic variant may contribute to tumor development or progression, as it is associated with different expression levels in tumor types. Prognostic: The passage notes that molecular alterations in gliomas are linked to clinical phenotypes and can predict outcomes, such as overall survival, indicating a prognostic relationship.
Gene→Variant (gene-first): 7015:CGGA 94) in the TCGA
Genes: 7015
Variants: CGGA 94) in the TCGA
In the M6620-carboplatin combination cohort, a confirmed RECISTv1.1 PR was observed in a 54-year-old woman with heavily pretreated metastatic high-grade serous ovarian cancer, who was treated at the combination RP2D. Bio
[Paragraph-level] PMCID: PMC7499606 Section: RESULTS PassageIndex: 18
Evidence Type(s): Oncogenic, Predictive
Justification: Oncogenic: The TP53 Y220C missense mutation is described as a "deleterious somatic mutation," indicating its contribution to tumor development or progression. Predictive: The passage discusses the patient's response to various therapies, including PARP inhibitors and the M6620-carboplatin combination therapy, suggesting that the Y220C variant may correlate with treatment response.
Gene→Variant (gene-first): 7157:Y220C
Genes: 7157
Variants: Y220C
Among the 87 patients of the study population, BRAF was mutated in 13 cases (15%). KRAS codons 61, 146 and BRAF V600E mutations were mutually exclusive. None of the patients bearing BRAF mutation responded to the treatme
[Paragraph-level] PMCID: PMC2736831 Section: RESULTS PassageIndex: 10
Evidence Type(s): Predictive, Prognostic, Oncogenic
Justification: Predictive: The passage indicates that none of the patients with the BRAF V600E mutation responded to the treatment, suggesting a correlation between the variant and resistance to therapy. Prognostic: The passage reports that BRAF mutation is associated with significantly shorter overall survival (OS) and a trend towards shorter progression-free survival (PFS), indicating its impact on disease outcome independent of therapy. Oncogenic: The BRAF V600E mutation is described as a somatic variant that is part of the study population's tumor mutations, contributing to tumor development or progression.
Gene→Variant (gene-first): 673:V600E
Genes: 673
Variants: V600E
In June 2013, profiling of sample 2 (tumor cell content 80%) using matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry (detailed in the Methods section) showed a heterozygous somatic
[Paragraph-level] PMCID: PMC5002925 Section: RESULTS PassageIndex: 6
Evidence Type(s): Oncogenic, Functional
Justification: Oncogenic: The passage discusses heterozygous somatic mutations, including ERBB2 p.L755S, APC p.Q1429fs, and BRAF p.N518S, which are associated with tumor development and progression, indicating their oncogenic potential. Functional: The passage mentions that the biological effect of the detected mutations was predicted using algorithms, suggesting an alteration in molecular or biochemical function related to these variants.
Gene→Variant (gene-first): 2064:p.L755S 673:p.N518S 673:p.N581S 324:p.Q1429fs
Genes: 2064 673 324
Variants: p.L755S p.N518S p.N581S p.Q1429fs
A 35-yr-old male, who was treated with a laparoscopic low anterior resection in June 2008 for a stage I (pT2N0M0) KRAS and NRAS wild-type, moderately differentiated, microsatellite stable rectal adenocarcinoma, developed
[Paragraph-level] PMCID: PMC5002925 Section: RESULTS PassageIndex: 3
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the treatment response to therapies such as trastuzumab and FOLFIRI, which are influenced by the presence of specific somatic mutations, indicating a correlation between the variants and treatment response. Oncogenic: The passage identifies somatic mutations in the tumors that are associated with tumor development and progression, particularly noting the likely activating mutation in the ERBB2 p.L755S variant.
Gene→Variant (gene-first): 673:c.1742A>G 2064:c.2264T>C 324:c.4285delC 673:p.Asn581Ser 324:p.Gln1429fs 2064:p.L755S 2064:p.Leu755Ser 673:p.N581S 324:p.Q1429fs
Genes: 673 2064 324
Variants: c.1742A>G c.2264T>C c.4285delC p.Asn581Ser p.Gln1429fs p.L755S p.Leu755Ser p.N581S p.Q1429fs
NTRK-fused gliomas in our cohort demonstrated concurrent aberrations involving CDKN2A/2B, TERT promoter, TP53, PTEN, EGFR, ATRX, RB1, IDH1, polysomy 7, ROS1, PIK3CA, NF1, and MDM4. The frequency of these genetic aberrati
[Paragraph-level] PMCID: PMC7362646 Section: RESULTS PassageIndex: 11
Evidence Type(s): Oncogenic
Justification: Oncogenic: The passage discusses the IDH1 p.R132H mutation as part of the genetic aberrations detected in gliomas, indicating its contribution to tumor development or progression in the context of high-grade gliomas.
Gene→Variant (gene-first): 3417:p.R132H
Genes: 3417
Variants: p.R132H
Although first-line crizotinib treatment leads to clinical benefit in ROS1+ lung cancer, high prevalence of crizotinib-resistant ROS1-G2032R mutation and progression in the central nervous system (CNS) represents a thera
[Paragraph-level] PMCID: PMC10283448 Section: ABSTRACT PassageIndex: 2
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the high prevalence of the crizotinib-resistant ROS1-G2032R mutation and its implications for treatment response, indicating a correlation with resistance to therapy. Oncogenic: The mention of the ROS1-G2032R mutation in the context of crizotinib resistance suggests that it contributes to tumor progression, which aligns with the definition of an oncogenic variant.
Gene→Variant (gene-first): 6098:G2032R
Genes: 6098
Variants: G2032R
Targeted sequencing results show a common driver mutation KRAS p.G12V (8.72%) along with two splicing mutations of DDR gene PALB2 in her resected primary lesion (online supplementary table S1). No alterations of other ma
[Paragraph-level] PMCID: PMC7342819 Section: RESULTS PassageIndex: 2
Evidence Type(s): Diagnostic, Predisposing, Oncogenic
Justification: Diagnostic: The passage discusses the identification of the KRAS p.G12V mutation and the PALB2 mutations in the context of a primary lesion, indicating their association with the disease. Predisposing: The PALB2 c.3114-1G>A mutation is explicitly described as a germline mutation detected in peripheral blood cells, suggesting it confers inherited risk for developing disease. Oncogenic: The PALB2 c.2514+1G>C mutation is described as a somatic mutation, which is associated with tumor development in the context of the primary lesion.
Gene→Variant (gene-first): 79728:c.2514+1G>C 79728:c.3114-1G>A 3845:p.G12V
Genes: 79728 3845
Variants: c.2514+1G>C c.3114-1G>A p.G12V
To further explore potential functions of these SNPs, we performed the eQTL analysis for selected SNPs and mRNA expression of their corresponding genes in cancer tissues by using TCGA dataset. As shown in Figure 3, the a
[Paragraph-level] PMCID: PMC7099049 Section: RESULTS PassageIndex: 13
Evidence Type(s): Functional, Prognostic
Justification: Functional: The passage discusses how the alleles of rs16879870 and rs854936 are associated with increased mRNA expression levels of their corresponding genes, indicating an alteration in molecular function. Prognostic: The passage reports that higher expression levels of the genes GJB7 and RTN4R correlate with worse prognosis in HNSCC patients, indicating a relationship with disease outcome independent of therapy.
Gene→Variant (gene-first): NA:rs16879870 NA:rs854936
Genes: NA
Variants: rs16879870 rs854936
Furthermore, stratification analyses were conducted to examine whether the effects of risk genotypes on death with HNSCC was modified by sex, age, smoking, drinking status, and clinical stage. However, the heterogeneity
[Paragraph-level] PMCID: PMC7099049 Section: RESULTS PassageIndex: 11
Evidence Type(s): Prognostic
Justification: Prognostic: The passage discusses the effects of risk genotypes, including rs2761591, on death with HNSCC, indicating a correlation with disease outcome.
Gene→Variant (gene-first): 341019:rs2761591
Genes: 341019
Variants: rs2761591
ROC model was built to assess the ability of NRG in prediction of HNSCC survival by using the area under the curve (AUC). We constructed two models to compare their ability, one for clinical variables and the other for b
[Paragraph-level] PMCID: PMC7099049 Section: RESULTS PassageIndex: 9
Evidence Type(s): Prognostic, Predictive
Justification: Prognostic: The passage discusses the ability of a model to predict survival in HNSCC, indicating a correlation between the variant and disease outcome. Predictive: The mention of using NRG in a prediction model for HNSCC survival suggests a relationship with treatment response or sensitivity, aligning with predictive evidence.
Gene→Variant (gene-first): 2264:AUC from 0
Genes: 2264
Variants: AUC from 0
To provide a better estimation of the hazards of survival, the risk genotypes (i.e., rs16879870 CA+AA, rs2641256 AA, rs2761591 GA, and rs854936 AC) were combined into one variable as the number of risk genotypes (NRG), w
[Paragraph-level] PMCID: PMC7099049 Section: RESULTS PassageIndex: 7
Evidence Type(s): Prognostic, Diagnostic
Justification: Prognostic: The passage discusses how the number of risk genotypes (NRG) correlates with the hazard of death in patients with HNSCC, indicating a relationship between the variants and disease outcome. Diagnostic: The variants are used to define and classify patients into groups based on the number of risk genotypes, which is associated with survival outcomes in HNSCC.
Gene→Variant (gene-first): NA:rs16879870 388325:rs2641256 341019:rs2761591 NA:rs854936
Genes: NA 388325 341019
Variants: rs16879870 rs2641256 rs2761591 rs854936
In the discovery stage, univariate and multivariable Cox regression analysis were further performed to evaluate the effects on risk of death for each of selected SNPs (Table 2), with adjusting of age, gender, smoking, dr
[Paragraph-level] PMCID: PMC7099049 Section: RESULTS PassageIndex: 6
Evidence Type(s): Prognostic, Diagnostic
Justification: Prognostic: The passage discusses the association of specific SNP genotypes with survival outcomes in HNSCC, indicating that these variants correlate with risk of death independent of therapy. Diagnostic: The passage mentions the classification performance of risk genotypes of selected SNPs, suggesting their use in defining or classifying disease risk.
Gene→Variant (gene-first): NA:rs16879870 388325:rs2641256 341019:rs2761591 NA:rs854936
Genes: NA 388325 341019
Variants: rs16879870 rs2641256 rs2761591 rs854936
As shown in Supplementary Figure 1, after QC, we performed Cox proportional hazards regression models to assess associations of 31,075 qualified genetic variants with HNSCC survival, with adjustment for age, gender, smok
[Paragraph-level] PMCID: PMC7099049 Section: RESULTS PassageIndex: 5
Evidence Type(s): Prognostic
Justification: Prognostic: The passage discusses the correlation of specific SNPs with HNSCC patients' survival, indicating that these variants are associated with disease outcome independent of therapy.
Gene→Variant (gene-first): NA:rs16879870 388325:rs2641256 341019:rs2761591 NA:rs854936
Genes: NA 388325 341019
Variants: rs16879870 rs2641256 rs2761591 rs854936
Conclusion: Our findings suggested that the SNPs (rs16879870, rs2641256, rs2761591, rs854936) might play a crucial role in prognosis of HNSCC.
[Paragraph-level] PMCID: PMC7099049 Section: ABSTRACT PassageIndex: 4
Evidence Type(s): Prognostic
Justification: Prognostic: The passage indicates that the SNPs are suggested to play a crucial role in the prognosis of HNSCC, which correlates with disease outcome.
Gene→Variant (gene-first): NA:rs16879870 388325:rs2641256 341019:rs2761591 NA:rs854936
Genes: NA 388325 341019
Variants: rs16879870 rs2641256 rs2761591 rs854936
Results: After combining the result of the two stages, 4 SNPs were significantly associated with HNSCC survival (rs16879870 at 6q14.3: adjusted HR = 2.02, 95%CI = 1.50-2.73, P = 3.88 x 10-6; rs2641256 at 17p13.2: adjuste
[Paragraph-level] PMCID: PMC7099049 Section: ABSTRACT PassageIndex: 3
Evidence Type(s): Prognostic, Functional
Justification: Prognostic: The passage discusses the association of SNPs with HNSCC survival, indicating that these variants correlate with disease outcome, specifically overall survival, independent of therapy. Functional: The passage mentions that the genotype of rs16879870 and rs854936 is significantly associated with the expression of specific genes in cancer tissues, suggesting that these variants alter molecular function.
Gene→Variant (gene-first): NA:rs16879870 388325:rs2641256 341019:rs2761591 NA:rs854936
Genes: NA 388325 341019
Variants: rs16879870 rs2641256 rs2761591 rs854936
We recently reported the results of a glioblastoma clinical trial with EGFR kinase inhibitors which associated clinical responses to the coexpression of EGFRvIII and PTEN. To investigate whether clinical responses might
[Paragraph-level] PMCID: PMC1702556 Section: RESULTS PassageIndex: 17
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the association of the R108K variant with clinical responses to EGFR kinase inhibitors, indicating a correlation with treatment response. Oncogenic: The R108K variant is identified in gliomas, suggesting its potential role in tumor development or progression, particularly in the context of EGFR amplification.
Gene→Variant (gene-first): 1956:R108K
Genes: 1956
Variants: R108K
The presence of identical missense mutations in multiple patient samples and their oncogenicity in standard transformation assays suggest that these mutants play a role in gliomagenesis. It also raises the question wheth
[Paragraph-level] PMCID: PMC1702556 Section: RESULTS PassageIndex: 16
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses how the presence of EGFR missense mutants, including L858R and L861Q, may sensitize transformed cells to EGFR kinase inhibitors, indicating a correlation with treatment response. Oncogenic: The identical missense mutations are described as having oncogenicity and playing a role in gliomagenesis, suggesting that these somatic variants contribute to tumor development.
Gene→Variant (gene-first): 1956:L858R 1956:L861Q 1956:T790M
Genes: 1956
Variants: L858R L861Q T790M
We also expressed selected EGFR mutants (R108K, T263P, A289V, G598V, L861Q) in murine hematopoietic cells (Ba/F3 cells) which do not express any EGFR family members but otherwise retain functional properties of the EGF-s
[Paragraph-level] PMCID: PMC1702556 Section: RESULTS PassageIndex: 14
Evidence Type(s): Functional
Justification: Functional: The passage discusses how the EGFR mutants (R108K, T263P, A289V, G598V, L861Q) alter the molecular function of the EGF-signaling pathway, specifically showing increased tyrosine phosphorylation and differences in receptor downregulation in response to EGF stimulation.
Gene→Variant (gene-first): 1956:A289V 1956:G598V 1956:L861Q 1956:R108K 1956:T263P
Genes: 1956
Variants: A289V G598V L861Q R108K T263P
Signal transduction through EGFR is determined by its basal catalytic activity, receptor activation by ligand, and signal termination through intracellular compartmentalization of the receptor-ligand complex, receptor de
[Paragraph-level] PMCID: PMC1702556 Section: RESULTS PassageIndex: 13
Evidence Type(s): Functional
Justification: Functional: The examination of other EGFR missense mutants (T263P, G598V, L861Q) also shows an increase in phosphotyrosine content, suggesting that these variants similarly affect the molecular function of the receptor.
Gene→Variant (gene-first): 1956:A289V 1956:G598V 1956:L861Q 1956:T263P
Genes: 1956
Variants: A289V G598V L861Q T263P
To further analyze the oncogenic potential of the EGFR mutants, NIH-3T3 subclones stably expressing the same missense mutant receptors (encoding R108K, T263P, A289V, G598V, and L861Q) were inoculated subcutaneously into
[Paragraph-level] PMCID: PMC1702556 Section: RESULTS PassageIndex: 11
Evidence Type(s): Oncogenic
Justification: Oncogenic: The passage describes how NIH-3T3 cells expressing the EGFR missense mutants (R108K, T263P, A289V, G598V, and L861Q) produced large tumors in mice, indicating that these variants contribute to tumor development.
Gene→Variant (gene-first): 1956:A289V 1956:G598V 1956:L861Q 1956:R108K 1956:T263P
Genes: 1956
Variants: A289V G598V L861Q R108K T263P
To test the oncogenicity of the glioma-related EGFR missense mutations, we transduced NIH-3T3 fibroblasts with retroviruses encoding either wild-type EGFR or selected EGFR missense mutants (encoding R108K, T263P, A289V,
[Paragraph-level] PMCID: PMC1702556 Section: RESULTS PassageIndex: 10
Evidence Type(s): Oncogenic
Justification: Oncogenic: The passage discusses the oncogenicity of EGFR missense mutations, indicating that the expression of these variants (R108K, T263P, A289V, G598V, and L861Q) in NIH-3T3 cells leads to anchorage-independent colony formation, a hallmark of tumorigenic behavior.
Gene→Variant (gene-first): 1956:A289V 1956:G598V 1956:L861Q 1956:R108K 1956:T263P
Genes: 1956
Variants: A289V G598V L861Q R108K T263P
To define which fraction of the EGFR pool represented the mutant allele in gliomas with EGFR missense mutations, we employed a PCR-cloning strategy previously used by our laboratories for mutation detection in clinical s
[Paragraph-level] PMCID: PMC1702556 Section: RESULTS PassageIndex: 5
Evidence Type(s): Diagnostic, Oncogenic
Justification: Diagnostic: The passage discusses the prevalence of specific EGFR missense mutations (R108K, T263P, A289V, and G598V) in gliomas, indicating their association with the disease and their representation in the receptor pool, which supports their use in defining or classifying the disease. Oncogenic: The mention of EGFR missense mutations in the context of gliomas suggests that these somatic variants contribute to tumor development or progression, as they are associated with the receptor pool in tumor samples.
Gene→Variant (gene-first): 1956:A289V 1956:G598V 1956:R108K 1956:T263P
Genes: 1956
Variants: A289V G598V R108K T263P
In all, we identified EGFR missense mutations in 14.4% (19/132) of glioblastomas, 12.5% (1/8) of glioblastoma cell lines, and none (0/11) in lower-grade gliomas. Only one tumor sample harbored a missense mutation in the
[Paragraph-level] PMCID: PMC1702556 Section: RESULTS PassageIndex: 4
Evidence Type(s): Diagnostic, Oncogenic, Predisposing
Justification: Diagnostic: The passage discusses the identification of EGFR missense mutations in glioblastomas and their association with the disease, indicating that these mutations can be used to classify or define the tumor type. Oncogenic: The passage mentions that the identified EGFR mutations contribute to tumor development in glioblastomas, particularly noting the presence of somatic mutations in the tumor samples. Predisposing: The passage specifies that one of the mutations (E330K) was identified as germline, indicating it confers inherited risk for developing disease.
Gene→Variant (gene-first): 1956:A289 1956:A289D 1956:A289T 1956:E330K 1956:L861Q 1956:R108 1956:R324L
Genes: 1956
Variants: A289 A289D A289T E330K L861Q R108 R324L
Four human NSCLC cell lines were employed, expressing either of the following forms of the EGFR: (i) the wild-type receptor (QG56 cells), (ii) a mutant with an exon 19 in-frame deletion (HCC827 cells), (iii) a mutant wit
[Paragraph-level] PMCID: PMC4385014 Section: ABSTRACT PassageIndex: 4
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the sensitivity of NSCLC cell lines with specific EGFR mutations (L858R and T790M) to the anti-proliferative effect of erlotinib, indicating a correlation with treatment response. Oncogenic: The presence of the L858R and T790M mutations in the cell lines suggests that these somatic variants contribute to tumor development or progression, as they are associated with specific cancer cell lines.
Gene→Variant (gene-first): 1956:L858R 1956:T790M
Genes: 1956
Variants: L858R T790M
Four patients harbored hotspot PIK3CA mutations most commonly seen in cancer. Two of these patients had a mosaic p.Glu542Lys mutation. Patient LR12-183 had a novel constellation of features including megalencephaly with
[Paragraph-level] PMCID: PMC5019182 Section: RESULTS PassageIndex: 19
Evidence Type(s): Diagnostic, Oncogenic
Justification: Diagnostic: The passage discusses the presence of specific PIK3CA mutations in patients with distinct clinical features, indicating that these mutations are associated with certain syndromes, such as linear nevus sebaceous or Schimmelpenning syndrome and CLOVES syndrome. Oncogenic: The passage mentions that the PIK3CA mutations are "hotspot" mutations commonly seen in cancer, suggesting that these somatic variants contribute to tumor development or progression.
Gene→Variant (gene-first): 5290:p.Glu542Lys 5290:p.Glu545Lys 5290:p.His1047Arg
Genes: 5290
Variants: p.Glu542Lys p.Glu545Lys p.His1047Arg
Patient LR12-070 had congenital hemihypertrophy, epidermal nevi, and lipomatous overgrowth of the trunk that was characteristically milder than CLOVES (Figure 4, E-G). He also had overlying capillary malformations, and m
[Paragraph-level] PMCID: PMC5019182 Section: RESULTS PassageIndex: 17
Evidence Type(s): Diagnostic, Oncogenic
Justification: Diagnostic: The passage discusses the presence of the p.Glu453Lys and p.Gly914Arg mutations in patients with specific congenital conditions, indicating their association with the phenotypes observed, which supports their use in defining or classifying the disease. Oncogenic: The p.Glu453Lys and p.Gly914Arg mutations are described in the context of patients with congenital overgrowth syndromes, suggesting a role in tumor development or progression, particularly in the context of somatic mutations.
Gene→Variant (gene-first): 5290:p.Glu453Lys 5290:p.Gly914Arg
Genes: 5290
Variants: p.Glu453Lys p.Gly914Arg
Several patients (n = 7) had novel phenotypes with features either overlapping MCAP but lacking megalencephaly or suggesting a milder variant of CLOVES. Patient LR15-238 had mild somatic hemihypertrophy and cutaneous vas
[Paragraph-level] PMCID: PMC5019182 Section: RESULTS PassageIndex: 16
Evidence Type(s): Diagnostic, Oncogenic
Justification: Diagnostic: The passage discusses the presence of specific mutations (p.Arg93Gln, p.Gly106Val, p.Cys378Tyr) in patients with phenotypes that overlap with or suggest variants of MCAP, indicating that these mutations are associated with defining or classifying the disease. Oncogenic: The passage describes the mutations as somatic variants present in patients with specific phenotypes, suggesting their contribution to tumor development or progression, particularly in the context of the patients' conditions.
Gene→Variant (gene-first): 5290:p.Arg93Gln 5290:p.Cys378Tyr 5290:p.Gly106Val
Genes: 5290
Variants: p.Arg93Gln p.Cys378Tyr p.Gly106Val
Most individuals with mosaic PIK3CA mutations in our cohort (n = 50) had classic features of MCAP, characterized by brain overgrowth (megalencephaly) and cutaneous vascular malformations, with variable body overgrowth, c
[Paragraph-level] PMCID: PMC5019182 Section: RESULTS PassageIndex: 14
Evidence Type(s): Diagnostic, Predisposing
Justification: Diagnostic: The passage discusses individuals with mosaic PIK3CA mutations, including the p.Glu726Lys variant, in the context of classic features of MCAP, indicating its role in defining or classifying the disease. Predisposing: The passage mentions that several patients with the p.Glu726Lys mutation had various clinical findings associated with MCAP, suggesting an inherited risk for developing this condition.
Gene→Variant (gene-first): 5290:p.Glu726Lys
Genes: 5290
Variants: p.Glu726Lys
Most of these mutations are proven or predicted to have a gain-of-function (GOF) mechanism, and oncogenic mutations at all of these amino acid sites have been seen in COSMIC. Published functional studies demonstrate a GO
[Paragraph-level] PMCID: PMC5019182 Section: RESULTS PassageIndex: 10
Evidence Type(s): Oncogenic, Diagnostic
Justification: Oncogenic: The passage discusses mutations that are proven or predicted to have a gain-of-function mechanism, indicating that these somatic variants contribute to tumor development or progression. Diagnostic: The mention of Glu545Ala and Glu545Lys mutations being detected in individuals with undefined "Cowden-like" features suggests an association with a specific disease or phenotype, supporting their use in diagnosis.
Gene→Variant (gene-first): 5290:Glu545Ala 5290:Glu545Lys 5290:p.Ala1035Thr 5290:p.Ala1035Val 5290:p.Asn345Lys 5290:p.Asn345Thr 5290:p.Gln546His 5290:p.Gln546Lys 5290:p.Gln546Pro 5290:p.Glu545Asp 5290:p.Glu545Gly 5290:p.Glu545Lys 5290:p.Tyr1021Cys 7249:p.Tyr1021His
Genes: 5290 7249
Variants: Glu545Ala Glu545Lys p.Ala1035Thr p.Ala1035Val p.Asn345Lys p.Asn345Thr p.Gln546His p.Gln546Lys p.Gln546Pro p.Glu545Asp p.Glu545Gly p.Glu545Lys p.Tyr1021Cys p.Tyr1021His
Overall, we identified 29 PIK3CA mutations in 72 individuals. We also reviewed published data on PIK3CA mutations in developmental pediatric disorders (all phenotypes except for cancer; Figure 2). When added to our data,
[Paragraph-level] PMCID: PMC5019182 Section: RESULTS PassageIndex: 9
Evidence Type(s): Diagnostic, Oncogenic
Justification: Diagnostic: The passage discusses the association of PIK3CA mutations with developmental pediatric disorders, indicating that these mutations are used to classify or define the disease phenotypes. Oncogenic: The mention of PIK3CA mutations, particularly the hotspot mutations, suggests their role in tumor development or progression, as they are frequently observed in affected individuals.
Gene→Variant (gene-first): 5290:p.Glu542Lys 5290:p.Glu545Lys 5290:p.Glu726Lys 5290:p.Gly914Arg 5290:p.His1047Arg
Genes: 5290
Variants: p.Glu542Lys p.Glu545Lys p.Glu726Lys p.Gly914Arg p.His1047Arg
Clinical testing identified several more patients with PIK3CA mutations. Mutations in 6 individuals were detected by targeted NGS using the Agilent SureSelect Capture technology. Another 5 were identified using standard-
[Paragraph-level] PMCID: PMC5019182 Section: RESULTS PassageIndex: 8
Evidence Type(s): Diagnostic
Justification: Diagnostic: The passage discusses the identification of mutations in patients, including the p.Arg93Gln variant, suggesting its association with specific cases and indicating its role in defining or confirming a disease.
Gene→Variant (gene-first): 5290:p.Arg93Gln
Genes: 5290
Variants: p.Arg93Gln
We identified 29 mutations of PIK3CA, including 16 novel mutations that have not been previously identified in developmental disorders, to our knowledge. Oncogenic mutations at all of these amino acid residues were prese
[Paragraph-level] PMCID: PMC5019182 Section: RESULTS PassageIndex: 5
Evidence Type(s): Oncogenic, Functional
Justification: Oncogenic: The passage discusses mutations of PIK3CA, including p.Glu545Lys and p.His1047Arg, which are identified as oncogenic mutations contributing to tumor development or progression, as indicated by their presence in the Catalogue of Somatic Mutations in Cancer (COSMIC). Functional: The passage mentions the alternative allele percentages (AAP) of the mutations, indicating that these variants may alter molecular or biochemical function, as evidenced by the variation in AAPs across different sample types.
Gene→Variant (gene-first): 5290:p.Glu545Lys 5290:p.His1047Arg
Genes: 5290
Variants: p.Glu545Lys p.His1047Arg
We then tested CHMFL-KIT-031 in the BaF3-TEL-KIT-V559D inoculated mouse model. Through IP injection, the compound displayed a dose-dependent slow down of the tumor progression and 100 mg/kg/day treatment achieved 68.5% t
[Paragraph-level] PMCID: PMC5762309 Section: RESULTS PassageIndex: 11
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the response of the tumor to the treatment with CHMFL-KIT-031, indicating a correlation between the V559D variant and the sensitivity to this specific therapy, as evidenced by tumor growth inhibition. Oncogenic: The V559D variant is implicated in tumor progression, as the passage describes its role in a mouse model where the variant is present and the tumor's response to treatment is evaluated.
Gene→Variant (gene-first): 3815:V559D
Genes: 3815
Variants: V559D
CHMFL-KIT-031 inhibits the tumor growth in BaF3-TEL-KIT-V559D cell inoculated in vivo model
[Paragraph-level] PMCID: PMC5762309 Section: RESULTS PassageIndex: 10
Evidence Type(s): Oncogenic, Predictive
Justification: Oncogenic: The variant V559D is discussed in the context of tumor growth inhibition, indicating that it contributes to tumor development or progression in the specified cell model. Predictive: The mention of CHMFL-KIT-031 inhibiting tumor growth suggests a correlation between the V559D variant and response to this specific therapy.
Gene→Variant (gene-first): 3815:V559D
Genes: 3815
Variants: V559D
In order to better define CHMFL-KIT-031's inhibitory effect against KIT V559D mutant, we then tested it with purified KIT wt/V559D kinase protein by ADP-Glo assay (Figure 2A). The results showed that it could potently in
[Paragraph-level] PMCID: PMC5762309 Section: RESULTS PassageIndex: 9
Evidence Type(s): Predictive, Functional
Justification: Predictive: The passage discusses the inhibitory effect of CHMFL-KIT-031 against the KIT V559D mutant, indicating a correlation with response to therapy, as evidenced by the IC50 values and selectivity over the wild-type KIT. Functional: The variant KIT V559D is shown to alter the molecular function by affecting the phosphorylation of specific sites and downstream mediators, demonstrating its role in biochemical activity as tested in various assays.
Gene→Variant (gene-first): 3815:V559D
Genes: 3815
Variants: V559D
CHMFL-KIT-031 selectively inhibits the KIT V559D mutant over KIT wt
[Paragraph-level] PMCID: PMC5762309 Section: RESULTS PassageIndex: 8
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage indicates that CHMFL-KIT-031 selectively inhibits the KIT V559D mutant, suggesting a correlation with response to therapy. Oncogenic: The mention of the KIT V559D mutant in the context of selective inhibition implies that this somatic variant contributes to tumor development or progression.
Gene→Variant (gene-first): 3815:V559D
Genes: 3815
Variants: V559D
Then we used the DiscoverX's KINOMEScan platform to further examine CHMFL-KIT-031's kinome-wide selectivity profile. The results showed that it exhibited a great selectivity among 468 kinases/mutants at the concentration
[Paragraph-level] PMCID: PMC5762309 Section: RESULTS PassageIndex: 7
Evidence Type(s): Predictive, Functional
Justification: Predictive: The passage discusses the binding and selectivity of CHMFL-KIT-031 to the V559D, L576P, and A829P variants, indicating their potential response to therapy, particularly in the context of inhibitor selectivity. Functional: The results indicate that the variants (V559D, L576P, A829P) alter the binding characteristics of the compound CHMFL-KIT-031, suggesting a change in molecular function related to kinase activity.
Gene→Variant (gene-first): 3815:A829P 3815:L576P 3815:V559D
Genes: 3815
Variants: A829P L576P V559D
In order to confirm the selectivity observed in the anti-proliferation assay of the transformed BaF3 cells, we then examined the inhibitory effect of CHMFL-KIT-031 for the KIT wt/mutant auto-phosphorylation at Y703, Y719
[Paragraph-level] PMCID: PMC5762309 Section: RESULTS PassageIndex: 5
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses how the KIT V559D mutant affects phosphorylation at specific sites, indicating that the variant alters molecular function related to protein activity. Oncogenic: The context of the passage suggests that the KIT V559D variant contributes to tumor development or progression, as it is involved in the anti-proliferation assay of transformed cells.
Gene→Variant (gene-first): 3815:V559D
Genes: 3815
Variants: V559D
CHMFL-KIT-031 potently inhibits KIT auto-phosphorylation in BaF3-TEL-KIT-V559D cells
[Paragraph-level] PMCID: PMC5762309 Section: RESULTS PassageIndex: 4
Evidence Type(s): Functional
Justification: Functional: The passage indicates that the variant V559D alters the molecular function of the KIT protein by affecting its auto-phosphorylation activity in specific cells.
Gene→Variant (gene-first): 3815:V559D
Genes: 3815
Variants: V559D
Through screening a panel of in-house made structure focused type II lead compounds prepared during development of KIT kinase inhibitors with KIT-V559D permanently transformed BaF3 cells, we found that CHMFL-KIT-031 (Fig
[Paragraph-level] PMCID: PMC5762309 Section: RESULTS PassageIndex: 3
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the response of various KIT variants, including V559D, L576P, and others, to different therapies such as CHMFL-KIT-031 and Imatinib, indicating their correlation with treatment sensitivity and resistance. Oncogenic: The variants mentioned, particularly V559D and L576P, are described in the context of their role in transforming BaF3 cells, suggesting that they contribute 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
CHMFL-KIT-031 selectively inhibits the proliferation of BaF3-TEL-KIT-V559D cells
[Paragraph-level] PMCID: PMC5762309 Section: RESULTS PassageIndex: 2
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage indicates that CHMFL-KIT-031 selectively inhibits the proliferation of cells with the V559D variant, suggesting a correlation with response to this specific therapy. Oncogenic: The mention of the V559D variant in the context of inhibiting cell proliferation implies that it contributes to tumor development or progression, as it is associated with a specific cell line used in cancer research.
Gene→Variant (gene-first): 3815:V559D
Genes: 3815
Variants: V559D
Given the prevalence of RIT1 mutation in primary human lung adenocarcinomas, we hypothesized that human lung adenocarcinoma cell lines may also harbor mutations in RIT1 and that identification of these cell lines would f
[Paragraph-level] PMCID: PMC4150988 Section: RESULTS PassageIndex: 11
Evidence Type(s): Oncogenic, Diagnostic
Justification: Oncogenic: The passage discusses the presence of the p.M90I mutation in lung adenocarcinoma cell lines and its association with human primary lung adenocarcinomas, indicating that this somatic variant contributes to tumor development or progression. Diagnostic: The p.M90I mutation is mentioned as being seen in human primary lung adenocarcinomas, suggesting its role in defining or classifying the disease.
Gene→Variant (gene-first): 6016:p.M90I
Genes: 6016
Variants: p.M90I
RIT1 mutation is mutually exclusive with mutations in other RAS/RTK-pathway genes, so we hypothesized that RIT1 may activate PI3K and MEK. To investigate the signaling changes induced by mutated RIT1, we expressed wild-t
[Paragraph-level] PMCID: PMC4150988 Section: RESULTS PassageIndex: 9
Evidence Type(s): Oncogenic, Functional
Justification: Oncogenic: The passage discusses how the RIT1 Q40L mutation contributes to tumor development by activating MEK and ERK pathways, indicating its role in oncogenic signaling. Functional: The variant Q40L alters the molecular function of RIT1, as it induces phosphorylation of MEK and ERK, demonstrating a change in biochemical activity associated with the mutation.
Gene→Variant (gene-first): 6016:Q40L
Genes: 6016
Variants: Q40L
To test whether mutated RIT1 is capable of inducing cellular transformation, we expressed wild-type or mutated RIT1 cDNA constructs in NIH3T3 cells and assayed the ability of these cells to form colonies in soft agar. A
[Paragraph-level] PMCID: PMC4150988 Section: RESULTS PassageIndex: 7
Evidence Type(s): Oncogenic, Functional
Justification: Oncogenic: The passage discusses how mutated RIT1 variants, including Q79L, G12V, and L858R, induce cellular transformation and tumor formation, indicating their role in tumor development. Functional: The passage describes the ability of specific RIT1 mutations to induce colony formation in soft agar, suggesting that these variants alter the molecular function of RIT1 in a way that promotes transformation.
Gene→Variant (gene-first): 3845:G12V 1956:L858R 6016:Q40 6016:Q40L 6016:Q79L
Genes: 3845 1956 6016
Variants: G12V L858R Q40 Q40L Q79L
We surveyed recent exome sequencing data from other diverse cancer types to determine whether RIT1 is mutated in malignancies other than lung adenocarcinoma. Most tumor types had no mutations, or rare RIT1 variants of un
[Paragraph-level] PMCID: PMC4150988 Section: RESULTS PassageIndex: 6
Evidence Type(s): Diagnostic, Oncogenic
Justification: Diagnostic: The passage discusses the presence of the RIT1 p.M90I variant in different cancer types, indicating its association with malignancies, which supports its use in defining or classifying disease subtypes. Oncogenic: The mention of somatic RIT1 mutations in myeloid malignancies and their overlap with mutations in lung adenocarcinoma suggests that these variants contribute to tumor development or progression.
Gene→Variant (gene-first): 6016:F82L 6016:M90I 6016:p.M90I
Genes: 6016
Variants: F82L M90I p.M90I
All seven samples with switch II domain RIT1 mutations lacked oncogenic driver mutations in EGFR, KRAS, BRAF, ERBB2, HRAS, NRAS and MAP2K1. This pattern of mutational mutual exclusivity is consistent with the possibility
[Paragraph-level] PMCID: PMC4150988 Section: RESULTS PassageIndex: 5
Evidence Type(s): Oncogenic
Justification: Oncogenic: The passage suggests that RIT1 switch II domain mutations, including p.R122L, may function as oncogenes in lung adenocarcinoma, indicating a role in tumor development or progression.
Gene→Variant (gene-first): 6016:p.R122L
Genes: 6016
Variants: p.R122L
Recurrent alteration of RIT1 alanine 77 was also observed; one of the ten mutated samples from this analysis harbored a p.A77P mutation and an additional TCGA sample (TCGA-73-4666) harbored a p.A77S mutation. TCGA-73-466
[Paragraph-level] PMCID: PMC4150988 Section: RESULTS PassageIndex: 4
Evidence Type(s): Diagnostic, Predisposing
Justification: Diagnostic: The passage discusses the recurrent alteration of RIT1 alanine 77 and mentions that one of the mutated samples harbored a p.A77P mutation, indicating its association with tumor classification. Predisposing: The passage suggests that p.A77S may represent a rare germline variant, indicating a potential inherited risk for disease, although it is noted to be unlikely.
Gene→Variant (gene-first): NA:alanine 77 6016:p.A77P 6016:p.A77S
Genes: NA 6016
Variants: alanine 77 p.A77P p.A77S
In total, non-synonymous somatic mutations of RIT1 were identified in 10/413 (2.4%) lung adenocarcinomas subjected to whole exome sequencing (Figure 1a, Supplementary Table 1). Mutations in RIT1 consisted of missense mut
[Paragraph-level] PMCID: PMC4150988 Section: RESULTS PassageIndex: 3
Evidence Type(s): Oncogenic
Justification: Oncogenic: The passage discusses non-synonymous somatic mutations of RIT1, including the p.M90I variant, in the context of lung adenocarcinomas, indicating that these mutations contribute to tumor development or progression.
Gene→Variant (gene-first): 6016:p.M90I
Genes: 6016
Variants: p.M90I
Since our study goal was to identify potential therapeutically relevant events, the novel loss of function mutation in ERRFI1 (E384X) detected in Patient 3's metastatic, recurrent/refractory SIC (Table S1) warranted addi
[Paragraph-level] PMCID: PMC3923676 Section: RESULTS PassageIndex: 16
Evidence Type(s): Oncogenic, Functional
Justification: Oncogenic: The passage discusses a novel loss of function mutation (E384X) in ERRFI1 that is associated with a patient's metastatic tumor, indicating that this somatic variant contributes to tumor development or progression. Functional: The passage mentions nearly complete loss of function of ERRFI1 due to the E384X mutation, suggesting that this variant alters the molecular or biochemical function of the protein.
Gene→Variant (gene-first): 672:E384X
Genes: 672
Variants: E384X
In addition to the variations identified in genes acting in EGFR and/or FGFR signaling pathways, we also report multiple sSNVs and copy number variations (CNVs) ( Figure 4 ) in genes such as HDAC1, TP53, MDM2 and AKT1, a
[Paragraph-level] PMCID: PMC3923676 Section: RESULTS PassageIndex: 6
Evidence Type(s): None
Justification: Not enough information in this passage.
Gene→Variant (gene-first): 1767:G C
Genes: 1767
Variants: G C
We identified 327 somatic coding mutations, with an average of 55 mutations/tumor (range 34-112), within our cohort ( Table 1 , Figure 1 ). Nonsynonymous single nucleotide variations were the predominant class in all of
[Paragraph-level] PMCID: PMC3923676 Section: RESULTS PassageIndex: 3
Evidence Type(s): Oncogenic, Predictive
Justification: Oncogenic: The variant E384X in ERRFI1 is described as being overexpressed in a tumor, indicating its potential role in tumor development or progression. Predictive: The passage discusses the therapeutic relevance of FGFR2 fusions and their treatment with FGFR inhibitors, suggesting a correlation with response to therapy.
Gene→Variant (gene-first): 672:E384X
Genes: 672
Variants: E384X
Advanced cholangiocarcinoma continues to harbor a difficult prognosis and therapeutic options have been limited. During the course of a clinical trial of whole genomic sequencing seeking druggable targets, we examined si
[Paragraph-level] PMCID: PMC3923676 Section: ABSTRACT PassageIndex: 1
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the use of erlotinib, an EGFR kinase inhibitor, in a patient with the ERRFI1 E384X mutation, noting rapid and robust disease regression, indicating a correlation between the variant and response to therapy. Oncogenic: The E384X variant in ERRFI1 is described as a somatic mutation that inactivates a negative regulator of EGFR activation, suggesting its contribution to tumor development or progression.
Gene→Variant (gene-first): 672:E384X
Genes: 672
Variants: E384X
In one of every four or five cases of breast cancer, the human epidermal growth factor receptor-2 (HER2) gene is overexpressed. These carcinomas are known as HER2-positive. HER2 overexpression is linked to an aggressive
[Paragraph-level] PMCID: PMC7081042 Section: ABSTRACT PassageIndex: 1
Evidence Type(s): Predictive, Diagnostic, Oncogenic
Justification: Predictive: The passage discusses how certain HER2 mutations, such as S310F, S310Y, R678Q, D769H, and I767M, correlate with favorable outcomes and good responses to anti-HER2 therapy, indicating their predictive value for treatment efficacy. Diagnostic: The passage mentions the identification of HER2 SNPs in HER2-positive breast cancer patients and their relationship with clinical outcomes, suggesting that these variants can be used to classify or define the disease subtype. Oncogenic: The passage indicates that somatic mutations in HER2 are linked to resistance to anti-HER2 therapy, suggesting that these mutations contribute to tumor development or progression.
Gene→Variant (gene-first): 2064:D769H 2064:D769Y 2064:I767M 1956:K753I 2064:L755S 2064:R678Q 2064:S310F 2064:S310Y 2064:V842I
Genes: 2064 1956
Variants: D769H D769Y I767M K753I L755S R678Q S310F S310Y V842I
Diffuse intrinsic pontine glioma (DIPG) is the main cause of brain tumour-related death in children. In the majority of cases diagnosis is based on clinical and MRI findings, resulting in the scarcity of pre-treatment sp
[Paragraph-level] PMCID: PMC4159563 Section: ABSTRACT PassageIndex: 1
Evidence Type(s): Diagnostic, Oncogenic
Justification: Diagnostic: The K27M-H3 mutation is described as being exclusively found in tumors with specific WHO grade II-IV astrocytoma histology, indicating its role in classifying and defining the disease subtype. Oncogenic: The passage indicates that the K27M-H3 mutation is associated with tumors that behave clinically as high-grade astrocytomas, suggesting its contribution to tumor development or progression.
Gene→Variant (gene-first): 90:K27M
Genes: 90
Variants: K27M
The mutation frequency of TYK2 in T-ALL cell lines compared to primary T-ALL samples was substantially different, with a high mutation rate of TYK2 in cell lines, but only a low mutation rate in primary samples. To deter
[Paragraph-level] PMCID: PMC3366948 Section: RESULTS PassageIndex: 22
Evidence Type(s): Oncogenic, Functional
Justification: Oncogenic: The passage discusses the presence of TYK2 mutations in T-ALL cell lines and suggests that these mutations may not represent an oncogenic event important for leukemia development in vivo, indicating a potential role in tumor progression. Functional: The analysis of the transforming properties of the TYK2 variants in Ba/F3 cells indicates that the variants do not show major differences in function compared to wild type TYK2, suggesting an assessment of molecular function.
Gene→Variant (gene-first): 4486:A35V 5395:C192Y 7297:R1027H
Genes: 4486 5395 7297
Variants: A35V C192Y R1027H
Interestingly, 4 of the 15 sequenced patient samples contain a variation in TET1. The TET gene family (TET1, TET2, TET3) of epigenetic regulators is important for the hematology field because of the observation of TET2 m
[Paragraph-level] PMCID: PMC3366948 Section: RESULTS PassageIndex: 18
Evidence Type(s): Oncogenic
Justification: Oncogenic: The variant H1297Y is described as a somatic variant confirmed in a patient case, indicating its contribution to tumor development or progression in the context of T-ALL.
Gene→Variant (gene-first): 80312:H1297Y
Genes: 80312
Variants: H1297Y
We identified several mutations in JAK2 and JAK3 in both cell lines and patient samples. All JAK kinases, except TYK2 (see below), are known oncogenes in leukemia and activating mutations and translocations affecting JAK
[Paragraph-level] PMCID: PMC3366948 Section: RESULTS PassageIndex: 15
Evidence Type(s): Oncogenic, Functional
Justification: Oncogenic: The passage describes that the M511I mutation transformed IL3 dependent 32D cells and induced T-ALL in mice, indicating its role in tumor development. Additionally, the A572V mutation was shown to transform cytokine dependent hematopoietic cells and induce leukemia in mice, further supporting its oncogenic potential. Functional: The passage discusses how specific mutations in JAK3, such as A572T and A572V, alter the function of the protein, as evidenced by their ability to transform cells and induce leukemia, indicating a change in molecular or biochemical function.
Gene→Variant (gene-first): 3718:A572 3718:A572T 3718:A572V 3718:M511I
Genes: 3718
Variants: A572 A572T A572V M511I
In the BEACON CRC study, encorafenib plus cetuximab improved OS, ORR, and progression-free survival in previously treated patients in the metastatic setting compared with standard chemotherapy. Based on the primary and u
[Paragraph-level] PMCID: PMC8078423 Section: ABSTRACT PassageIndex: 8
Evidence Type(s): Predictive, Diagnostic
Justification: Predictive: The passage discusses the improved overall survival (OS), objective response rate (ORR), and progression-free survival associated with the treatment of encorafenib plus cetuximab in patients with BRAF V600E mCRC, indicating a correlation with therapy response. Diagnostic: The mention of BRAF V600E in the context of metastatic colorectal cancer (mCRC) suggests its role in defining or classifying a specific disease subtype, as it is associated with a particular treatment regimen.
Gene→Variant (gene-first): 673:V600E
Genes: 673
Variants: V600E
In this open-label, phase III trial, 665 patients with BRAF V600E-mutant mCRC were randomly assigned 1:1:1 to receive triplet, doublet, or control. Primary end points were OS and independently reviewed ORR comparing trip
[Paragraph-level] PMCID: PMC8078423 Section: ABSTRACT PassageIndex: 4
Evidence Type(s): Predictive, Diagnostic
Justification: Predictive: The passage discusses a trial involving patients with BRAF V600E-mutant mCRC and mentions endpoints related to overall survival (OS) and objective response rate (ORR), indicating a correlation with treatment response. Diagnostic: The mention of "BRAF V600E-mutant mCRC" implies that the variant is used to classify or define a specific subtype of cancer, which aligns with diagnostic evidence.
Gene→Variant (gene-first): 673:V600E
Genes: 673
Variants: V600E
BEACON CRC evaluated encorafenib plus cetuximab with or without binimetinib versus investigators' choice of irinotecan or FOLFIRI plus cetuximab in patients with BRAFV600E-mutant metastatic colorectal cancer (mCRC), afte
[Paragraph-level] PMCID: PMC8078423 Section: ABSTRACT PassageIndex: 2
Evidence Type(s): Predictive, Diagnostic
Justification: Predictive: The passage discusses the correlation of the BRAFV600E variant with improved overall survival and objective response rate in patients treated with specific therapies, indicating its predictive value for treatment response. Diagnostic: The mention of BRAFV600E in the context of metastatic colorectal cancer suggests its role in defining or classifying a specific subtype of the disease, supporting its use as a diagnostic marker.
Gene→Variant (gene-first): 673:BRAFV600E
Genes: 673
Variants: BRAFV600E
The data from safety, efficacy, and PK studies suggest that abivertinib dose levels of 150 to 300 mg twice a day may represent the efficacious range while 350 mg twice a day dose had the least favorable safety profile, t
[Paragraph-level] PMCID: PMC9365372 Section: RESULTS PassageIndex: 13
Evidence Type(s): Predictive, Diagnostic
Justification: Predictive: The passage discusses the overall response rate (ORR) and disease control rate (DCR) in patients with the T790M variant, indicating a correlation with treatment response to abivertinib. Diagnostic: The mention of T790M+ in the context of evaluating patient cohorts suggests that this variant is used to classify or define a specific group of patients for treatment assessment.
Gene→Variant (gene-first): 1956:T790M
Genes: 1956
Variants: T790M
Of the 132 evaluable patients with EGFR T790M+ treated across all dose levels, responses were observed with 100 to 300 mg twice-a-day doses, and with highest ORR in 200 mg twice a day (40.0%, 8/20) and 300 mg twice a day
[Paragraph-level] PMCID: PMC9365372 Section: RESULTS PassageIndex: 9
Evidence Type(s): Predictive
Justification: Predictive: The passage discusses the response rates of patients with the T790M variant treated with specific doses of abivertinib, indicating a correlation between the variant and treatment response.
Gene→Variant (gene-first): 1956:T790M
Genes: 1956
Variants: T790M
A total of 878 Chinese patients with NSCLC were screened (Fig. 1). In phase I, a total of 231 patients were screened and 140 patients who received treatment were included in this analysis; in phase II, 647 patients were
[Paragraph-level] PMCID: PMC9365372 Section: RESULTS PassageIndex: 3
Evidence Type(s): Diagnostic, Predictive
Justification: Diagnostic: The passage indicates that T790M-negative status was a major reason for exclusion from the study, suggesting its role in defining eligibility for treatment in patients with NSCLC. Predictive: The mention of T790M-negative status as a reason for screening failure implies that the presence of this variant may correlate with resistance to the treatment being studied (abivertinib).
Gene→Variant (gene-first): 1956:T790M
Genes: 1956
Variants: T790M
In this follow-up report, we present updated information regarding a previously reported pediatric patient with a World Health Organization grade I ganglioglioma harboring a BRAF p.T599dup mutation (Cold Spring Harb Mol
[Paragraph-level] PMCID: PMC8040738 Section: ABSTRACT PassageIndex: 1
Evidence Type(s): Predictive, Diagnostic, Oncogenic
Justification: Predictive: The passage discusses the use of combination targeted therapy with a selective BRAF inhibitor and MEK inhibitor for a patient with a BRAF mutation, indicating a correlation with treatment response. Diagnostic: The identification of BRAF alterations is mentioned as a means to assist clinicians in determining alternative targeted treatment strategies, suggesting its role in classifying or defining the tumor type. Oncogenic: The passage implies that the BRAF mutations contribute to tumor development or progression, as the patient has a ganglioglioma harboring a BRAF mutation.
Gene→Variant (gene-first): 673:V600E 673:p.T599dup 673:p.V600E
Genes: 673
Variants: V600E p.T599dup p.V600E
Three other FFPE samples from NSCLC patients were also investigated by LCN-HRM for mutations in EGFR exons 19 (TX13) and 21 (TX49, TX86). After sequencing the LCM-HRM positive products, multiple non-identical sequence va
[Paragraph-level] PMCID: PMC2766370 Section: RESULTS PassageIndex: 10
Evidence Type(s): None
Justification: Not enough information in this passage.
Gene→Variant (gene-first): 1956:c.2192G>A 1956:c.2224G>A 1956:c.2488G>A
Genes: 1956
Variants: c.2192G>A c.2224G>A c.2488G>A
Non-identical KRAS sequence variants were also detected in five of the other LCN-HRM reactions; c.22G>A, c.32C>A, c.38G>A, c.59C>T and c.100C>T. These transitional changes have not been previously reported, except those
[Paragraph-level] PMCID: PMC2766370 Section: RESULTS PassageIndex: 9
Evidence Type(s): None
Justification: Not enough information in this passage.
Gene→Variant (gene-first): 3845:C>A 3845:C>T 3845:G>A 7157:c.100C>T 1956:c.22G>A 3845:c.32C>A 3845:c.38 (codon 13) 3845:c.38G>A 7157:c.59C>T
Genes: 3845 7157 1956
Variants: C>A C>T G>A c.100C>T c.22G>A c.32C>A c.38 (codon 13) c.38G>A c.59C>T
Four NSCLC samples extracted from FFPE tissues were tested by LCN-HRM to investigate the cause of discrepant results between HRM and sequencing. TX450 was negative by sequencing but positive by HRM for KRAS exon 2. After
[Paragraph-level] PMCID: PMC2766370 Section: RESULTS PassageIndex: 8
Evidence Type(s): Diagnostic, Oncogenic
Justification: Diagnostic: The passage discusses the detection of the KRAS mutation c.34G>T (p.G12C) in NSCLC samples, indicating its association with the disease and its role in characterizing the mutation through sequencing. Oncogenic: The variant c.34G>T (p.G12C) is mentioned in the context of being a mutation detected in NSCLC samples, suggesting its contribution to tumor development or progression.
Gene→Variant (gene-first): 3845:c.34G>T 3845:p.G12C
Genes: 3845
Variants: c.34G>T p.G12C
HCT116 and NCI-H1650 DNA dilutions with a 5% mutant allele frequency were sequencing negative for KRAS exon 2 missense and EGFR exon 19 deletion mutations respectively (Figure 1, data not shown for EGFR exon 19). The sam
[Paragraph-level] PMCID: PMC2766370 Section: RESULTS PassageIndex: 6
Evidence Type(s): Diagnostic, Oncogenic
Justification: Diagnostic: The passage discusses the identification of specific mutations (c.38G>A and delE746_A750) in the context of sequencing and testing, indicating their role in defining or confirming the presence of these mutations in the respective cell lines. Oncogenic: The mention of the delE746_A750 EGFR mutation in the context of tumor cell lines (NCI-H1650) suggests that this somatic variant contributes to tumor development or progression.
Gene→Variant (gene-first): 3845:c.38G>A 3845:delE746_A750 EGFR
Genes: 3845
Variants: c.38G>A delE746_A750 EGFR
The relative sensitivity of mutation detection by dideoxynucleotide sequencing and HRM was compared using dilutions of HCT116 DNA (heterozygous for the c.38G>A KRAS mutation) in normal DNA. To ensure the maximum accuracy
[Paragraph-level] PMCID: PMC2766370 Section: RESULTS PassageIndex: 3
Evidence Type(s): None
Justification: Not enough information in this passage.
Gene→Variant (gene-first): 3845:c.38G>A
Genes: 3845
Variants: c.38G>A
The HDR functional dataset was completely concordant with three other functional studies that evaluated the ability for a human BRCA2 variant to restore survival of Brca2 null mouse embryonic stem cells (Table S1). In an
[Paragraph-level] PMCID: PMC8008494 Section: RESULTS PassageIndex: 9
Evidence Type(s): Predictive, Functional
Justification: Predictive: The passage discusses the sensitivity of specific BRCA2 variants to PARP inhibitors, indicating a correlation with response to therapy. Functional: The passage describes how the BRCA2 variants influence the ability to restore survival in mouse embryonic stem cells and their functional classification based on drug sensitivity assays.
Gene→Variant (gene-first): 675:c.8723T>G 675:c.8905G>A 675:p.Val2908Gly 675:p.Val2969Met
Genes: 675
Variants: c.8723T>G c.8905G>A p.Val2908Gly p.Val2969Met
HDR assay results are provided for 53 variants, along with previously reported data for 199 variants, for a total of 252 missense variants (Figure 1; Table 1; Table S1). Among the 252 variants, 90 were considered non-fun
[Paragraph-level] PMCID: PMC8008494 Section: RESULTS PassageIndex: 3
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses how specific variants alter the function of the protein, indicating that certain amino acid substitutions result in loss of function or maintain functionality, which is characteristic of functional evidence. Oncogenic: The context of the variants being associated with loss of function in a cancer-related gene (BRCA2) suggests that these somatic variants contribute to tumor development or progression.
Gene→Variant (gene-first): NA:2619 from Trp to Gly 675:2723 from Asp to Asn 353:7522G>A 353:7807G>T 353:7874G>A 353:7879A>G NA:Leu3180 353:Phe/Asn 353:c.7522G>C 675:c.7880T>A 675:c.9370A>C 675:c.9371A>T 675:c.9539T>C 675:p.Ala2603Ser 675:p.Arg2625Lys 675:p.Asn3124His 353:p.Gly2508Arg 675:p.Gly2508Ser 675:p.Ile2627Val
Genes: NA 675 353
Variants: 2619 from Trp to Gly 2723 from Asp to Asn 7522G>A 7807G>T 7874G>A 7879A>G Leu3180 Phe/Asn c.7522G>C c.7880T>A c.9370A>C c.9371A>T c.9539T>C p.Ala2603Ser p.Arg2625Lys p.Asn3124His p.Gly2508Arg p.Gly2508Ser p.Ile2627Val
The correlation of inhibition of ALK phosphorylation (Tyr1282/1283) was evaluated as a function of TPX-0131 plasma exposure analysis using the Ba/F3 CDX model harboring the EML4-ALK fusion with the G1202R/L1196M compound
[Paragraph-level] PMCID: PMC9398166 Section: RESULTS PassageIndex: 12
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the correlation of TPX-0131 treatment with tumor growth inhibition and suppression of ALK phosphorylation, indicating that the G1202R, L1196M, and L1198F variants are associated with resistance to therapy and response to treatment. Oncogenic: The variants G1202R, L1196M, and L1198F are described in the context of ALK resistance mutations, suggesting their role in tumor development or progression as they are associated with the EML4-ALK fusion in a cancer model.
Gene→Variant (gene-first): 238:G1202R 238:L1196M 238:L1198F
Genes: 238
Variants: G1202R L1196M L1198F
TGI and the pharmacodynamic modulation of ALK were performed in cell-derived xenograft (CDX) models for clinically relevant ALK mutants that limit the utility of previous generations of ALK inhibitors (e.g. SFM, compound
[Paragraph-level] PMCID: PMC9398166 Section: RESULTS PassageIndex: 11
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the response of tumor models harboring specific ALK mutations (G1202R, L1196M, L1198F) to the therapy TPX-0131, indicating a correlation between the variants and treatment efficacy. Oncogenic: The variants G1202R, L1196M, and L1198F are described in the context of tumor models, suggesting that they contribute to tumor development or progression as part of the EML4-ALK fusion.
Gene→Variant (gene-first): 238:G1202R 238:L1196M 238:L1198F
Genes: 238
Variants: G1202R L1196M L1198F
To confirm the results obtained from the cell proliferation assays, TPX-0131 and select other ALK inhibitors were evaluated in assays measuring pharmacodynamic modulation of ALK (autophosphorylation). TPX-0131 suppressed
[Paragraph-level] PMCID: PMC9398166 Section: RESULTS PassageIndex: 9
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses how the variants G1202R, L1196M, and L1198F correlate with the response to the ALK inhibitor TPX-0131, indicating their role in resistance to therapy. Oncogenic: The variants mentioned are part of ALK oncogenic fusion proteins, which are implicated in tumor development and progression, as evidenced by their evaluation in assays measuring ALK autophosphorylation.
Gene→Variant (gene-first): 238:G1202R 238:L1196M 238:L1198 238:L1198F
Genes: 238
Variants: G1202R L1196M L1198 L1198F
In cell proliferation assays, TPX-0131 was the most potent inhibitor against a range of EML4-ALK compound mutations (Table 2). TPX-0131 inhibited six of nine compound mutations with IC50 < 1 nmol/L, had IC50 < 10 nmol/L
[Paragraph-level] PMCID: PMC9398166 Section: RESULTS PassageIndex: 8
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the response of the ALK G1202R/G1269A/L1204V triple mutation to the TPX-0131 inhibitor, indicating a correlation with treatment sensitivity. Oncogenic: The mention of the EML4-ALK compound mutations, including G1202R, G1269A, and L1204V, in the context of cell proliferation assays suggests that these somatic variants contribute to tumor development or progression.
Gene→Variant (gene-first): 238:G1202R 238:G1269A 238:L1204V
Genes: 238
Variants: G1202R G1269A L1204V
To enable comparisons of TPX-0131 with previous generations of ALK inhibitors, a panel of matched cell lines was created that are dependent on ALK resistance mutations found in patients as well as other mutations that ma
[Paragraph-level] PMCID: PMC9398166 Section: RESULTS PassageIndex: 7
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the potency of TPX-0131 against various ALK mutations, indicating that the variant mutations correlate with the response to the therapy, specifically highlighting the differences in inhibition potency against different mutations. Oncogenic: The passage describes the use of engineered Ba/F3 cells expressing oncogenic EML4-ALK variants, indicating that these mutations contribute to tumor development or progression, as they are associated with resistance to ALK inhibitors.
Gene→Variant (gene-first): 238:C1156Y 238:G1202R 238:G1269A 238:G1269S 238:I1171N 238:I1171N/S 238:L1196M 238:L1198F 238:L1204V 238:S/T
Genes: 238
Variants: C1156Y G1202R G1269A G1269S I1171N I1171N/S L1196M L1198F L1204V S/T
Biochemical characterization of TPX-0131 potency against WT and mutant ALK was assessed in a panel of enzymatic assays with recombinant ALK kinase domains performed at 10 muM ATP (Table 1). TPX-0131 potently inhibited WT
[Paragraph-level] PMCID: PMC9398166 Section: RESULTS PassageIndex: 5
Evidence Type(s): Predictive, Functional
Justification: Predictive: The passage discusses the potency of TPX-0131 against various ALK mutations, indicating its effectiveness as a therapy for these specific variants, which correlates with treatment response. Functional: The passage describes the biochemical characterization of TPX-0131's inhibition of ALK mutations, focusing on its molecular properties and binding interactions that alter the function of the ALK protein.
Gene→Variant (gene-first): 238:C1156Y 238:D1203N 238:E1210K 238:F1174C 238:F1174L 238:F1174S 238:F1245C 238:G1202 238:G1202R 238:G1269A 238:G1269S 238:I1171N 238:L1152P 238:L1152R 238:L1196M 238:L1198F 238:R1275Q 238:S1206C 238:S1206R 238:T1151-L1152 insT 238:T1151M 238:V1180L
Genes: 238
Variants: C1156Y D1203N E1210K F1174C F1174L F1174S F1245C G1202 G1202R G1269A G1269S I1171N L1152P L1152R L1196M L1198F R1275Q S1206C S1206R T1151-L1152 insT T1151M V1180L
The most prevalent resistance mutations to second-generation ALK inhibitors (e.g., alectinib, brigatinib) are in the solvent front region (e.g., G1202; ref. 16). Molecular modeling illustrates that second-generation ALK
[Paragraph-level] PMCID: PMC9398166 Section: RESULTS PassageIndex: 3
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses resistance mutations, including G1202, in the context of second-generation ALK inhibitors and their reduced potency, indicating a correlation with treatment response. Oncogenic: The mention of G1202 as a resistance mutation suggests that it contributes to tumor development or progression by obstructing binding and reducing the efficacy of ALK inhibitors.
Gene→Variant (gene-first): 238:G1202
Genes: 238
Variants: G1202
It has reported that CREB is a direct target of PTEN where PTEN physically interacts with, and dephosphorylates CREB at Serine 133. Interestingly, cancerous cells have been shown to restore the CREB phosphorylation that
[Paragraph-level] PMCID: PMC6791388 Section: RESULTS PassageIndex: 14
Evidence Type(s): Predictive, Functional
Justification: Predictive: The passage discusses how increased phosphorylation of CREB at Ser133 may promote MEK inhibitor resistance, indicating a correlation with treatment response. Functional: The variant at Ser133 is described in the context of altering the phosphorylation state of CREB, which affects its molecular function and activity.
Gene→Variant (gene-first): 7157:S133 7157:Ser133 7157:Serine 133
Genes: 7157
Variants: S133 Ser133 Serine 133
The BCL-2 mutation G101V reduces venetoclax affinity and confers drug resistance in patients with chronic lymphocytic leukaemia. Here, the authors present crystal structures and biochemical analyses of venetoclax bound t
[Paragraph-level] PMCID: PMC6547681 Section: ABSTRACT PassageIndex: 2
Evidence Type(s): Predictive, Functional
Justification: Predictive: The variant G101V is associated with drug resistance to venetoclax in patients, indicating a correlation with treatment response. Functional: The passage discusses the biochemical analyses of the G101V mutant, revealing how it alters the affinity of venetoclax, which relates to its molecular function.
Gene→Variant (gene-first): 596:G101V
Genes: 596
Variants: G101V
Venetoclax is a first-in-class cancer therapy that interacts with the cellular apoptotic machinery promoting apoptosis. Treatment of patients suffering chronic lymphocytic leukaemia with this BCL-2 antagonist has reveale
[Paragraph-level] PMCID: PMC6547681 Section: ABSTRACT PassageIndex: 1
Evidence Type(s): Predictive, Functional
Justification: Predictive: The passage discusses the emergence of the G101V mutation in patients failing therapy with venetoclax, indicating a correlation between the variant and resistance to this specific therapy. Functional: The passage describes how the G101V mutation alters the binding of venetoclax to BCL-2, indicating a change in molecular function related to drug resistance.
Gene→Variant (gene-first): 596:E152 596:E152A 596:G101V 596:V101
Genes: 596
Variants: E152 E152A G101V V101
The efficacy of osimertinib against HER2 exon 19, p.L755P mutations and other HER2 exon 19 aberrations should be tested in clinical trials to determine its efficacy as a potential HER2 targeted treatment for patients har
[Paragraph-level] PMCID: PMC10183391 Section: RESULTS PassageIndex: 7
Evidence Type(s): Predictive, Diagnostic
Justification: Predictive: The passage discusses the efficacy of osimertinib as a potential treatment for patients harboring the p.L755P mutation, indicating a correlation with response to therapy. Diagnostic: The mention of "patients harboring these mutations" suggests that the p.L755P variant is used to classify or define a specific group of patients, indicating its role in diagnosis.
Gene→Variant (gene-first): 2064:p.L755P
Genes: 2064
Variants: p.L755P
Here we demonstrate for the first time in humans, that osimertinib was an effective and well tolerated treatment in a patient with stage IV NSCLC harboring HER2 exon 19, p.L755P mutation.
[Paragraph-level] PMCID: PMC10183391 Section: RESULTS PassageIndex: 5
Evidence Type(s): Predictive, Diagnostic
Justification: Predictive: The passage indicates that the p.L755P mutation is associated with an effective response to the treatment with osimertinib in a patient with stage IV NSCLC. Diagnostic: The passage mentions that the patient harbors the p.L755P mutation, which is used to classify the patient's disease subtype (HER2 exon 19 mutation in NSCLC).
Gene→Variant (gene-first): 2064:p.L755P
Genes: 2064
Variants: p.L755P
Osimertinib, a 3rd generation EGFR-TKI has been found in pre-clinical studies, both in vitro and in vivo, to have activity against various HER2 exon 19 aberrations, including HER2 exon 19, p.L755P mutations.
[Paragraph-level] PMCID: PMC10183391 Section: RESULTS PassageIndex: 4
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the activity of Osimertinib against the p.L755P mutation, indicating a correlation with response to therapy. Oncogenic: The mention of the p.L755P mutation in the context of HER2 exon 19 aberrations suggests that it contributes to tumor development or progression, as it is associated with a specific cancer-related mutation.
Gene→Variant (gene-first): 2064:p.L755P
Genes: 2064
Variants: p.L755P
We present a case of a 68-year-old female with stage IV NSCLC harboring a ERBB2 exon 19 c.2262_2264delinsTCC, p.(L755P) mutation treated with osimertinib, resulting in intra- and extracranial response.
[Paragraph-level] PMCID: PMC10183391 Section: RESULTS PassageIndex: 2
Evidence Type(s): Predictive, Diagnostic
Justification: Predictive: The passage discusses a patient treated with osimertinib, indicating that the variant correlates with a response to this specific therapy. Diagnostic: The variant is described as being present in a patient with stage IV NSCLC, suggesting its role in defining or classifying the disease.
Gene→Variant (gene-first): 2064:c.2262_2264delinsTCC 2064:p.(L755P)
Genes: 2064
Variants: c.2262_2264delinsTCC p.(L755P)
We found that ERBB2 E401G enhances C-terminal phosphorylation in a way similar to S310F. MD simulation analysis revealed that these variants maintain the stability of the EGFR-HER2 heterodimer in a ligand-independent man
[Paragraph-level] PMCID: PMC8881279 Section: ABSTRACT PassageIndex: 6
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses how the variants E401G and S310F alter molecular function by enhancing C-terminal phosphorylation and maintaining the stability of the EGFR-HER2 heterodimer. Oncogenic: The passage indicates that ERBB2 E401G-transduced cells exhibit increased tumor growth capacity in vivo, suggesting that this variant contributes to tumor development or progression.
Gene→Variant (gene-first): 2176:E401G 2064:S310F
Genes: 2176 2064
Variants: E401G S310F
ERBB2 E401G was selected as VUS for analysis because multiple software tools predicted its pathogenicity. We prepared ERBB2 expression vectors with the E401G variant as well as vectors with S310F and E321G, which are kno
[Paragraph-level] PMCID: PMC8881279 Section: ABSTRACT PassageIndex: 4
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses the evaluation of the phosphorylation of human epidermal growth factor receptor 2 and related proteins, as well as the investigation of the biological effects of the ERBB2 E401G variant, indicating an alteration in molecular function. Oncogenic: The mention of S310F and E321G as known activating mutations suggests that these variants contribute to tumor development or progression, aligning with the oncogenic evidence type.
Gene→Variant (gene-first): 7157:E321G 2176:E401G 2064:S310F
Genes: 7157 2176 2064
Variants: E321G E401G S310F
Dealing with variants of unknown significance (VUS) is an important issue in the clinical application of NGS-based cancer gene panel tests. We detected a novel ERBB2 extracellular domain VUS, c.1157A > G p.(E401G), in a
[Paragraph-level] PMCID: PMC8881279 Section: ABSTRACT PassageIndex: 2
Evidence Type(s): Functional
Justification: Functional: The passage discusses the aim to clarify the biological functions of the ERBB2 E401G variant, indicating an interest in how this variant alters molecular or biochemical function.
Gene→Variant (gene-first): 4609:1157A > G 2176:E401G
Genes: 4609 2176
Variants: 1157A > G E401G
Somatic mutations in the epidermal growth factor receptor (EGFR) are a major cause of non-small cell lung cancer. Among these structurally diverse alterations, exon 20 insertions represent a unique subset that rarely res
[Paragraph-level] PMCID: PMC11551396 Section: ABSTRACT PassageIndex: 3
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the drug sensitivity and resistance of the exon 20 insertion variants, indicating their correlation with response to specific therapies, particularly EGFR tyrosine kinase inhibitors. Oncogenic: The passage describes somatic mutations in the EGFR gene, specifically the exon 20 insertion variants, which contribute to tumor development in non-small cell lung cancer.
Gene→Variant (gene-first): 1956:L858R 1956:N771insSVD
Genes: 1956
Variants: L858R N771insSVD
Around 95% of patients with clinical features that meet the diagnostic criteria for von Hippel-Lindau disease (VHL) have a detectable inactivating germline variant in VHL. The VHL protein (pVHL) functions as part of the
[Paragraph-level] PMCID: PMC9402235 Section: ABSTRACT PassageIndex: 2
Evidence Type(s): Diagnostic, Oncogenic
Justification: Diagnostic: The passage discusses how the variant c.236A>G (p.Tyr79Cys) is associated with von Hippel-Lindau disease (VHL) and suggests that genetic testing for ELOC variants should be performed in individuals with suspected VHL disease, indicating its role in disease classification. Oncogenic: The variant is described as a de novo pathogenic variant identified in a proband with VHL disease and is linked to the development of renal cell carcinoma (RCC), suggesting its contribution to tumor development or progression.
Gene→Variant (gene-first): 3091:c.236A>G 3091:p.Tyr79Cys
Genes: 3091
Variants: c.236A>G p.Tyr79Cys
The above results suggest a bias against oncogenic mutations in the KrasC118S allele. While preliminary experiments revealed that ectopic KrasQ61L,C118S and KrasQ61L behaved rather similarly with regards to signaling, tr
[Paragraph-level] PMCID: PMC4234187 Section: RESULTS PassageIndex: 16
Evidence Type(s): Oncogenic, Functional
Justification: Oncogenic: The passage discusses the behavior of Kras mutations, specifically KrasC118S and KrasG13D, in the context of transformation and signaling, indicating their role in tumor development and progression. Functional: The analysis of P-Erk1/2 levels upon EGF treatment suggests that the KrasC118S variant alters molecular function related to signaling pathways, as evidenced by the immunoblotting results.
Gene→Variant (gene-first): 4843:C118 4843:C118S 3845:G13D 4893:Q61L
Genes: 4843 3845 4893
Variants: C118 C118S G13D Q61L
We next tested whether there was a bias of oncogenic mutations induced by urethane in either the native or C118S Kras allele in Kras+/C118S mice. To this end, RNA was extracted from 65 lung tumors from 20 Kras+/C118S mic
[Paragraph-level] PMCID: PMC4234187 Section: RESULTS PassageIndex: 15
Evidence Type(s): Oncogenic, Functional
Justification: Oncogenic: The passage discusses the identification of oncogenic mutations, specifically Q61R/L, in the context of tumor development in Kras+/C118S mice, indicating that these variants contribute to tumor progression. Functional: The mention of the C118S variant in the context of its allelic origin and mutation status suggests an alteration in molecular function related to the Kras gene, which is relevant to its role in oncogenesis.
Gene→Variant (gene-first): 4843:C118S 4893:Q61R 3845:Q61R/L
Genes: 4843 4893 3845
Variants: C118S Q61R Q61R/L
In the urethane-induced lung tumor model, typically only one Kras allele acquires an oncogenic mutation. While the oncogenic Kras allele is well established to promote tumorigenesis, the remaining non-oncogenic allele ha
[Paragraph-level] PMCID: PMC4234187 Section: RESULTS PassageIndex: 13
Evidence Type(s): Oncogenic, Functional
Justification: Oncogenic: The passage discusses the KrasG12D allele as promoting lung tumorigenesis, indicating its role in tumor development. Functional: The passage describes the C118S mutation's effect on the tumorigenic activity of the oncogenic Kras allele and its interaction with the non-oncogenic allele, suggesting a change in molecular function related to tumor suppression.
Gene→Variant (gene-first): 4843:C118S 3845:G12D
Genes: 4843 3845
Variants: C118S G12D
Similar tumorigenesis between KrasLSL-G12D/+ and KrasLSL-G12D/C118S mice
[Paragraph-level] PMCID: PMC4234187 Section: RESULTS PassageIndex: 12
Evidence Type(s): Oncogenic
Justification: Oncogenic: The passage indicates that the variants G12D and C118S are involved in similar tumorigenesis, suggesting that they contribute to tumor development or progression.
Gene→Variant (gene-first): 4843:C118S 3845:G12D
Genes: 4843 3845
Variants: C118S G12D
To assess whether there was also an impact on tumor progression, lesions were graded as being atypical adenomatous hyperplasia (AAH), adenoma (AD), or adenocarcinoma (AC) by histology (Supplementary Fig. 3). This analysi
[Paragraph-level] PMCID: PMC4234187 Section: RESULTS PassageIndex: 11
Evidence Type(s): Oncogenic, Functional
Justification: Oncogenic: The passage discusses the impact of the KrasC118S variant on tumor progression and its association with different tumor types, indicating that this somatic variant contributes to tumor development or progression. Functional: The analysis shows that the KrasC118S variant is associated with reduced P-Akt signaling, suggesting that it alters molecular function related to signaling pathways involved in tumor biology.
Gene→Variant (gene-first): 4843:C118S
Genes: 4843
Variants: C118S
Comparison of the number and size of visible surface lung lesions revealed that Kras+/C118S or KrasC118S/C118S mice developed fewer tumors with a smaller average tumor size, resulting in an overall reduction in tumor bur
[Paragraph-level] PMCID: PMC4234187 Section: RESULTS PassageIndex: 10
Evidence Type(s): Oncogenic, Functional
Justification: Oncogenic: The passage discusses how the KrasC118S variant contributes to tumor development by resulting in fewer tumors and smaller average tumor sizes in mice, indicating its role in tumor progression. Functional: The presence of the KrasC118S allele is shown to alter the tumor characteristics, specifically leading to a shift towards smaller tumors, which suggests an alteration in molecular or biochemical function related to tumor development.
Gene→Variant (gene-first): 4843:C118S
Genes: 4843
Variants: C118S
To determine the impact of the KrasC118S mutation on carcinogenesis, we assessed the effect of treating Kras+/+, Kras+/C118S, and KrasC118S/C118S mice with the carcinogen urethane (ethyl carbamate), which induces lung tu
[Paragraph-level] PMCID: PMC4234187 Section: RESULTS PassageIndex: 9
Evidence Type(s): Oncogenic, Functional
Justification: Oncogenic: The passage discusses the KrasC118S mutation in the context of its role in carcinogenesis and tumor development, particularly in relation to urethane-induced lung tumors characterized by oncogenic Q61R/L mutations in Kras. Functional: The passage implies that the KrasC118S mutation alters the molecular behavior of Kras in the context of tumorigenesis, as it is assessed for its impact on carcinogenesis and tumor development.
Gene→Variant (gene-first): 4843:C118S 3845:Q61R/L
Genes: 4843 3845
Variants: C118S Q61R/L
Identification of genotypes of 580 offspring from crossing Kras+/C118S mice revealed that there was no statistical difference between the observed frequency versus the expected Mendelian ratio of the three genotypes of K
[Paragraph-level] PMCID: PMC4234187 Section: RESULTS PassageIndex: 7
Evidence Type(s): Oncogenic, Prognostic
Justification: Oncogenic: The passage discusses the KrasC118S variant in the context of its role in mouse models, indicating that it does not lead to significant developmental or physiological defects, which suggests its involvement in tumor development or progression. Prognostic: The passage mentions the median lifespan of KrasC118S/C118S mice compared to Kras+/+ mice, indicating a potential correlation with disease outcome, although the difference was not statistically significant.
Gene→Variant (gene-first): 4843:C118S
Genes: 4843
Variants: C118S
KrasC118S/C118S mice appear normal
[Paragraph-level] PMCID: PMC4234187 Section: RESULTS PassageIndex: 6
Evidence Type(s): None
Justification: Not enough information in this passage.
Gene→Variant (gene-first): 4843:C118S
Genes: 4843
Variants: C118S
We confirmed that the strategy to introduce the G353>C transversion into the Kras gene did not overtly affect alternative splicing of terminal exons 4A and 4B, an important consideration as both splice forms are importan
[Paragraph-level] PMCID: PMC4234187 Section: RESULTS PassageIndex: 5
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses how the C118S mutation affects the ability of eNOS to stimulate the MAPK pathway and provides evidence of altered molecular function through immunoblot analysis of protein levels and activity. Oncogenic: The passage indicates that the C118S mutation is important for carcinogen-induced lung tumorigenesis, suggesting that it contributes to tumor development or progression.
Gene→Variant (gene-first): 4843:C118S 4843:G353>C 4846:S1177D
Genes: 4843 4846
Variants: C118S G353>C S1177D
To investigate the effect of mutating C118 on Ras function in vivo during tumorigenesis, a targeting vector was created to insert a single point mutation, namely a G353 transversion to C (G353>C) encoding the C118S mutat
[Paragraph-level] PMCID: PMC4234187 Section: RESULTS PassageIndex: 3
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses how the C118S mutation specifically blocks redox-dependent reactions that lead to Ras activation, indicating an alteration in molecular function. Oncogenic: The context of the study involves investigating the effect of the C118S mutation on Ras function during tumorigenesis, suggesting that this somatic variant contributes to tumor development or progression.
Gene→Variant (gene-first): 4843:C118 4843:C118S 4843:G353 transversion to C 4843:G353>C
Genes: 4843
Variants: C118 C118S G353 transversion to C G353>C
All the mutations were in the TK domain that is critical for EGFR activity (Figure 2). Sequence alignment of the human wild- type EGFR with the Pfam model of protein kinase domain indicates W731, E734, T785, C797, Y801,
[Paragraph-level] PMCID: PMC2970593 Section: RESULTS PassageIndex: 5
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses mutations in the TK domain of EGFR that are critical for its activity, indicating that these variants alter molecular function related to protein activity. Oncogenic: The context of the mutations being in the TK domain of EGFR suggests that they may contribute to tumor development or progression, as this domain is often implicated in oncogenic signaling pathways.
Gene→Variant (gene-first): 1956:C797 NA:E734 NA:T785 1956:E868 1956:L858 1956:R831 NA:W731 1956:Y801
Genes: 1956 NA
Variants: C797 E734 T785 E868 L858 R831 W731 Y801
We analyzed a cohort of MPM samples (n = 29) by DHPLC and sequencing analysis, and identified eight mutations in the tyrosine kinase domain (TKD) of EGFR. Of the 8 mutations in the TK domain, 7 were novel (W731L, E734Q,
[Paragraph-level] PMCID: PMC2970593 Section: RESULTS PassageIndex: 3
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage states that the L858R mutation was found to increase sensitivity to the EGFR inhibitor, Erlotinib, indicating a correlation with treatment response. Oncogenic: All mutations mentioned in the passage, including C797Y, E734Q, E868G, L831H, L858R, T785A, W731L, and Y801H, are described as somatic mutations that contribute to tumor development, as they were identified in the tyrosine kinase domain of EGFR in cancer samples.
Gene→Variant (gene-first): 1956:C797Y 1956:E734Q 1956:E868G 1956:L831H 1956:L858R 1956:T785A 1956:W731L 1956:Y801H
Genes: 1956
Variants: C797Y E734Q E868G L831H L858R T785A W731L Y801H
Since our data indicates that the SF3B1K700E mutation gives rise to an HR defect, we hypothesised that this could be exploited therapeutically to treat tumours that have acquired this mutation. To test this hypothesis, w
[Paragraph-level] PMCID: PMC7612475 Section: RESULTS PassageIndex: 19
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses how the SF3B1K700E mutation can be therapeutically targeted, indicating a correlation with treatment response to etoposide and olaparib, which are specific therapies. Oncogenic: The SF3B1K700E mutation is implicated in tumor development, as the passage describes its role in creating an HR defect and its effects on tumor growth in xenograft models.
Gene→Variant (gene-first): 23451:K700E
Genes: 23451
Variants: K700E
Lastly, it is known that following replication arrest, several proteins, including BRCA1 and BRCA2, are required for preventing uncontrolled nucleolytic degradation of damaged forks and loss of this function contributes
[Paragraph-level] PMCID: PMC7612475 Section: RESULTS PassageIndex: 17
Evidence Type(s): Oncogenic, Functional
Justification: Oncogenic: The passage discusses how the SF3B1 K700E variant contributes to cellular deficits characteristic of BRCA1/2 loss, indicating its role in tumor development or progression. Functional: The variant K700E is shown to alter the recruitment of Rad51 to replication forks and affects replication fork stability, demonstrating a change in molecular function.
Gene→Variant (gene-first): 23451:K700E
Genes: 23451
Variants: K700E
To assess whether the increased R-loops present in the SF3B1K700E mutant expressing cell line affects DNA replication, we examined replication fork dynamics using the DNA fibre assay (Figure 3B). Notably, this analysis r
[Paragraph-level] PMCID: PMC7612475 Section: RESULTS PassageIndex: 14
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses how the SF3B1K700E variant affects replication fork dynamics and efficiency of replication fork restart, indicating an alteration in molecular function related to DNA replication. Oncogenic: The context of the study involves assessing the impact of the SF3B1K700E mutation on cellular processes relevant to tumor development, such as replication fork dynamics, which suggests a role in oncogenesis.
Gene→Variant (gene-first): 23451:K700E
Genes: 23451
Variants: K700E
Our data clearly suggests a role for SF3B1 in the DDR, particularly in HR mediated DNA repair following DNA damage. However, we have also observed increased DSBs and reduced HR in unperturbed SF3B1K700E cells. Importantl
[Paragraph-level] PMCID: PMC7612475 Section: RESULTS PassageIndex: 13
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The D210N variant is described as being catalytically inactivated, which alters its ability to resolve R-loops, indicating a change in molecular function. Oncogenic: The passage discusses the role of the D210N variant in the context of R-loop accumulation and genome instability, which are associated with tumor development and progression.
Gene→Variant (gene-first): 246243:D210N
Genes: 246243
Variants: D210N
SF3B1K700E mutation induces unscheduled R-loops, stalled replication forks, and reduced replication fork protection and restart
[Paragraph-level] PMCID: PMC7612475 Section: RESULTS PassageIndex: 12
Evidence Type(s): Functional
Justification: Functional: The passage discusses how the K700E mutation alters molecular function by inducing unscheduled R-loops and affecting replication fork dynamics.
Gene→Variant (gene-first): 23451:K700E
Genes: 23451
Variants: K700E
To directly determine the impact of the SF3B1K700E mutation on HR, we assessed the formation and resolution of Rad51 foci, a key marker of HR function, in our isogenic models following IR induced DNA damage. Intriguingly
[Paragraph-level] PMCID: PMC7612475 Section: RESULTS PassageIndex: 9
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses how the SF3B1K700E mutation alters the molecular function of homologous recombination (HR) by affecting the formation and resolution of Rad51 foci, indicating a defect in the later stages of HR. Oncogenic: The SF3B1K700E mutation is implicated in tumor development or progression as it affects the ability of cells to resolve recombination intermediates, which is a critical process in maintaining genomic stability in cancer cells.
Gene→Variant (gene-first): 23451:K700E
Genes: 23451
Variants: K700E
To assess the biological impact of this deregulated splicing and export, we performed Ingenuity Pathway Analysis (IPA) on genes with 3ASS and SE in SF3B1K700E cells. Consistent with a role for SF3B1 in DNA repair, this a
[Paragraph-level] PMCID: PMC7612475 Section: RESULTS PassageIndex: 8
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses how the SF3B1K700E variant alters the ability of cells to resolve DNA double-strand breaks (DSBs) and impairs homologous recombination (HR) repair, indicating a change in molecular function related to DNA repair mechanisms. Oncogenic: The SF3B1K700E mutation is described as cancer-associated and is shown to contribute to defects in DNA repair, which is a characteristic of oncogenic variants that promote tumor development or progression.
Gene→Variant (gene-first): 23451:K700E
Genes: 23451
Variants: K700E
Mutations in SF3B1 have been identified across several cancer types. This key spliceosome component promotes the efficient mRNA splicing of thousands of genes including those with crucial roles in the cellular response t
[Paragraph-level] PMCID: PMC7612475 Section: ABSTRACT PassageIndex: 1
Evidence Type(s): Predictive, Functional
Justification: Predictive: The K700E mutation in SF3B1 increases cellular sensitivity to ionising radiation and various chemotherapeutic agents, including PARP inhibitors, indicating a correlation with treatment response. Functional: The K700E mutation alters HR efficiency and induces unscheduled R-loop formation, replication fork stalling, and defective replication fork restart, demonstrating an impact on molecular function.
Gene→Variant (gene-first): 23451:K700E
Genes: 23451
Variants: K700E
We report the discovery of the GATA2 gene as a new myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) predisposition gene. We found the same, novel heterozygous c.1061C>T (p.Thr354Met) missense mutation in the G
[Paragraph-level] PMCID: PMC3184204 Section: ABSTRACT PassageIndex: 1
Evidence Type(s): Predisposing, Diagnostic, Functional
Justification: Predisposing: The passage describes the discovery of the GATA2 gene as a predisposition gene for myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), indicating that the variants are associated with inherited risk for developing these diseases. Diagnostic: The variants are used to define and classify familial forms of MDS and AML, as they are reported to segregate with the disease in multiple families, which supports their role in diagnosis. Functional: The passage mentions that the mutations have differential effects on transactivation of target genes, cellular differentiation, apoptosis, and global gene expression, indicating that they alter molecular or biochemical function.
Gene→Variant (gene-first): 2624:c.1061C>T 2624:c.1063_1065delACA 2624:p.Thr354Met 6688:p.Thr355del
Genes: 2624 6688
Variants: c.1061C>T c.1063_1065delACA p.Thr354Met p.Thr355del
Advances in the understanding of the molecular basis for acute myeloid leukemia (AML) have generated new potential targets for treatment. Fms-like tyrosine kinase 3 (FLT3) is one of the most frequently mutated genes in A
[Paragraph-level] PMCID: PMC5613053 Section: ABSTRACT PassageIndex: 2
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the ability of gilteritinib to block mutated FLT3, including the D835Y and F691 mutations, and its correlation with improved survival in models of FLT3-driven AML, indicating a response to therapy. Oncogenic: The D835Y and F691 mutations in FLT3 are implicated in the pathogenesis of acute myeloid leukemia (AML), suggesting that these somatic variants contribute to tumor development or progression.
Gene→Variant (gene-first): 2322:D835Y 2322:F691
Genes: 2322
Variants: D835Y F691
Of the 106 variants tested, we classify 50 as Pathogenic, including 31 ASD. We further classify 10 variants, including 4 ASD, as Likely Pathogenic. We consider 24 variants to be Likely Benign, including 3 ASD: P354Q, T20
[Paragraph-level] PMCID: PMC7190743 Section: RESULTS PassageIndex: 25
Evidence Type(s): Diagnostic
Justification: Diagnostic: The passage discusses the classification of variants as Pathogenic and Likely Pathogenic, indicating their association with specific diseases or subtypes, which aligns with the definition of diagnostic evidence.
Gene→Variant (gene-first): 5728:A79T 5728:C211W 5728:E157G 5728:H123Q 5728:I135V 5728:I203V 5728:I400V 5728:K342N 5728:K402N 5728:L345V 5728:L70V 5728:M35V 5728:N117S 5728:N228S 5728:N340D 5728:N340H 5728:N356D 5728:P354Q 5728:Q298E 5728:S229T 5728:T202I 5728:T78A 5728:W274L 5728:Y176C 5728:Y180H 5728:Y65C
Genes: 5728
Variants: A79T C211W E157G H123Q I135V I203V I400V K342N K402N L345V L70V M35V N117S N228S N340D N340H N356D P354Q Q298E S229T T202I T78A W274L Y176C Y180H Y65C
PTEN functions as a negative regulator of the PI3-AKT signaling pathway by decreasing the pool of available PI(3,4,5)P3 via its lipid phosphatase activity, causing a reduction in the level of activated, phosphorylated AK
[Paragraph-level] PMCID: PMC7190743 Section: RESULTS PassageIndex: 16
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses how various PTEN variants, including A126D, A126P, C124S, G129E, H123Q, P354Q, P38H, Q396R, R130L, and R130Q, alter the molecular function of PTEN by affecting pAKT levels, indicating changes in biochemical activity. Oncogenic: The variants are described in the context of their effects on the PI3-AKT signaling pathway and their ability to exhibit loss of function (LoF) or gain of function (GoF), which are indicative of their roles in tumor development or progression.
Gene→Variant (gene-first): 5728:A126D 5728:A126P 5728:C124S 5728:G129E 5728:H123Q 5728:P354Q 5728:P38H 5728:Q396R 5728:R130L 5728:R130Q
Genes: 5728
Variants: A126D A126P C124S G129E H123Q P354Q P38H Q396R R130L R130Q
To identify molecular mechanisms underlying variable effects of MS variants, we measured impact on protein stability, a known mechanism of PTEN dysfunction. We measured PTEN protein abundance for WT and 97 variants teste
[Paragraph-level] PMCID: PMC7190743 Section: RESULTS PassageIndex: 14
Evidence Type(s): Functional
Justification: Functional: The passage discusses how the variants affect protein stability and abundance, indicating that they alter molecular function, which is supported by the use of western blot analysis and flow cytometry to measure these changes.
Gene→Variant (gene-first): 5728:H93Y 5728:P354Q 5728:R130L 5728:R14G 5728:R15S 5728:T78A
Genes: 5728
Variants: H93Y P354Q R130L R14G R15S T78A
Since ASD is a behaviorally diagnosed disorder, and deficits in sensory processing are a core feature of ASD present in >95% of cases, we tested the effects of PTEN variants on sensorimotor neural circuit function in an
[Paragraph-level] PMCID: PMC7190743 Section: RESULTS PassageIndex: 12
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses how PTEN variants affect sensorimotor neural circuit function and chemotaxis in C. elegans, indicating that these variants alter molecular or biochemical function. Oncogenic: The context of the passage suggests that the PTEN variants are involved in a pathway related to tumor development or progression, particularly given the focus on mutations in a cancer-related gene.
Gene→Variant (gene-first): 5728:A79T 5728:C124S 5728:D268E 5728:G132D 5728:P354Q 5728:T167N 5728:Y176C
Genes: 5728
Variants: A79T C124S D268E G132D P354Q T167N Y176C
Aberrant neuronal morphology and excitatory/inhibitory synapse balance are hallmarks of ASD, and ASD rodent models. Reducing PTEN expression results in increased neuronal growth, with larger soma size, increased dendriti
[Paragraph-level] PMCID: PMC7190743 Section: RESULTS PassageIndex: 10
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses how various PTEN variants, including C124S, I101T, G132D, D268E, and A79T, alter neuronal growth processes and synapse density, indicating that these variants affect molecular or biochemical functions in neuronal cultures. Oncogenic: The passage mentions that the PHTS variant A79T exhibits a gain-of-function (GoF) phenotype in axonal growth, suggesting that it contributes to tumor development or progression in the context of its association with ASD.
Gene→Variant (gene-first): 5728:A79T 5728:C124S 5728:D268E 5728:G132D 5728:I101T
Genes: 5728
Variants: A79T C124S D268E G132D I101T
We generated 88 transgenic lines of Drosophila melanogaster expressing WT human PTEN and 86 PTEN variants, each integrated into the attP2 locus, with attP2 used as an empty vector (EV) control, allowing quantitative comp
[Paragraph-level] PMCID: PMC7190743 Section: RESULTS PassageIndex: 8
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses how various PTEN variants, including C124S, G129E, N117S, and Q298E, alter developmental rates in Drosophila, indicating that these variants affect molecular or biochemical function related to insulin signaling and eclosion timing. Oncogenic: The mention of the known gain-of-function variant 4A inducing lethality suggests that some variants contribute to tumor development or progression, aligning with oncogenic behavior.
Gene→Variant (gene-first): 5728:C124S 5728:G129E 5728:N117S 5728:Q298E
Genes: 5728
Variants: C124S G129E N117S Q298E
We took advantage of the high-throughput capacity of the Saccharomyces cerevisiae synthetic dosage lethality screen as an unbiased assay to identify genetic interactions of PTEN. By overexpressing human WT PTEN (WT), emp
[Paragraph-level] PMCID: PMC7190743 Section: RESULTS PassageIndex: 5
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses how the C124S variant alters molecular interactions and functions within the context of PI3P metabolism and signaling, indicating a change in biochemical activity. Oncogenic: The C124S variant is described in the context of genetic interactions that may contribute to tumor development or progression, as it is involved in a synthetic dosage lethality screen related to PTEN's role in cancer biology.
Gene→Variant (gene-first): 5728:C124S
Genes: 5728
Variants: C124S
We selected PTEN MS and nonsense (NS) mutations identified in individuals with ASD, intellectual disability (ID), developmental delay (DD), somatic cancer and PHTS, as well as variants found among the general population
[Paragraph-level] PMCID: PMC7190743 Section: RESULTS PassageIndex: 3
Evidence Type(s): Diagnostic, Oncogenic, Functional
Justification: Diagnostic: The passage discusses the classification of variants, including C124S, G129E, R130X, and R335X, in relation to their association with conditions such as ASD, PHTS, and somatic cancer, indicating their role in defining or confirming these diseases. Oncogenic: The passage mentions that C124S and G129E have been found in somatic cancer, indicating that these variants contribute to tumor development or progression. Functional: The passage describes several variants, including C124S and G129E, as having well-characterized disruptions on protein function, indicating that they alter molecular or biochemical function.
Gene→Variant (gene-first): 5728:C124S 5728:G129E 5728:R130X 5728:R335X 5728:Y138L
Genes: 5728
Variants: C124S G129E R130X R335X Y138L
To clarify the relationship between CYP3A4 expression and resistance to FOLFIRI and cetuximab, we compared the expression levels of CYP3A4 in CRCs displaying different therapeutic responses (GEO data sets GSE13294 and GS
[Paragraph-level] PMCID: PMC3973211 Section: RESULTS PassageIndex: 12
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the relationship between p53 mutations (including R175H, R248W, R273H, R282W) and resistance to chemotherapy, specifically noting that cells with these mutations showed higher viability and increased IC50 for various drugs, indicating a correlation with drug resistance. Oncogenic: The passage implies that the p53 mutations contribute to tumor behavior by affecting cell response to chemotherapy, suggesting their role in tumor development or progression.
Gene→Variant (gene-first): 7157:R175H 7157:R248W 7157:R273H 7157:R282W
Genes: 7157
Variants: R175H R248W R273H R282W
The GSEA analysis revealed that most of the drug metabolism enzymes in association with p53 R248/R282 mutations are responsible for the clearance of chemotherapeutic drugs. Among these, the most relevant one was cytochro
[Paragraph-level] PMCID: PMC3973211 Section: RESULTS PassageIndex: 10
Evidence Type(s): Predictive, Functional
Justification: Predictive: The passage discusses the association between p53 mutations (R248, R282) and the expression of CYP3A4, a drug metabolism enzyme, indicating a correlation with drug clearance and potential response to chemotherapeutic drugs. Functional: The passage describes how p53 mutations (R248, R282) alter the expression levels of the CYP3A4 enzyme, demonstrating a change in molecular function related to drug metabolism.
Gene→Variant (gene-first): 7157:R175 7157:R175H 7157:R248 7157:R248W 7157:R273 7157:R273H 7157:R282 7157:R282W
Genes: 7157
Variants: R175 R175H R248 R248W R273 R273H R282 R282W
To probe the characteristic pathways associated with different p53-hotspot mutations, we selected the colorectal cancer (CRC) data set in TCGA as an example. The CRC cases contain more mortality-associated mutations (R24
[Paragraph-level] PMCID: PMC3973211 Section: RESULTS PassageIndex: 8
Evidence Type(s): Prognostic, Functional
Justification: Prognostic: The passage mentions that R248Q/W and R282W are associated with mortality, indicating a correlation with disease outcome. Functional: The passage discusses the enrichment of specific gene sets linked to cellular respiration and drug metabolism enzymes for certain mutations, suggesting alterations in molecular function.
Gene→Variant (gene-first): 7157:R175H 7157:R248Q/W 7157:R248W 7157:R273H 7157:R282W
Genes: 7157
Variants: R175H R248Q/W R248W R273H R282W
R248 and R282 mutations associate with drug metabolism enzymes
[Paragraph-level] PMCID: PMC3973211 Section: RESULTS PassageIndex: 7
Evidence Type(s): Diagnostic, Predictive
Justification: Diagnostic: The passage indicates that the R282 mutation is associated with drug metabolism enzymes, suggesting its role in defining or classifying a specific biological context related to drug metabolism. Predictive: The mention of the R282 mutation in relation to drug metabolism enzymes implies a potential correlation with response or sensitivity to therapies that involve these enzymes.
Gene→Variant (gene-first): 7157:R282
Genes: 7157
Variants: R282
We tested the association between R248/R282 mutations and cancer patient survival using an independent data set extracted from published literatures (data in Supplementary Table 1), and found these mutations are indeed a
[Paragraph-level] PMCID: PMC3973211 Section: RESULTS PassageIndex: 6
Evidence Type(s): Prognostic, Oncogenic
Justification: Prognostic: The passage discusses the association of R248 and R282 mutations with shorter patient survival, indicating a correlation with disease outcome independent of therapy. Oncogenic: The mention of mice carrying the humanized mutation on R248 exhibiting significantly shorter survival time suggests that this somatic variant contributes to tumor development or progression.
Gene→Variant (gene-first): 7157:R175 7157:R248 7157:R273 7157:R282
Genes: 7157
Variants: R175 R248 R273 R282
Kaplan-Meier survival analysis revealed that patients carrying p53 mutations on Arg248 and Arg282 residues had significantly shorter overall survival time than those carrying nonsense mutations (Figures 2a and b). Other
[Paragraph-level] PMCID: PMC3973211 Section: RESULTS PassageIndex: 4
Evidence Type(s): Prognostic, Oncogenic
Justification: Prognostic: The passage discusses how mutations at Arg248 and Arg282 correlate with significantly shorter overall survival times, indicating a relationship between these variants and disease outcome independent of therapy. Oncogenic: The mention of p53 mutations, including those at Arg248 and Arg282, suggests a role in tumor development or progression, as these mutations are associated with survival outcomes in cancer patients.
Gene→Variant (gene-first): 7157:Arg248 7157:Arg282 7157:G245 7157:R175 7157:R248 7157:R249S 7157:R273 7157:R282 7157:Y220
Genes: 7157
Variants: Arg248 Arg282 G245 R175 R248 R249S R273 R282 Y220
Mutations on Arg282 and Arg248 residues associate with shorter patient survival
[Paragraph-level] PMCID: PMC3973211 Section: RESULTS PassageIndex: 2
Evidence Type(s): Prognostic
Justification: Prognostic: The passage indicates that mutations at Arg282 and Arg248 are associated with shorter patient survival, which correlates with disease outcome independent of therapy.
Gene→Variant (gene-first): 7157:Arg248 7157:Arg282
Genes: 7157
Variants: Arg248 Arg282
Our next goal was to define the molecular signatures of each TSC hamartomatous lesion type using genome-wide DNA methylation and transcript profiling. Unsupervised clustering of DNA methylation array data revealed lesion
[Paragraph-level] PMCID: PMC5481739 Section: RESULTS PassageIndex: 12
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses the somatic DNMT3A-V716F mutation and its predicted effect on methyltransferase activity, indicating that the variant alters molecular function. Oncogenic: The mention of the somatic DNMT3A-V716F mutation in the context of a tumor suggests that it contributes to tumor development or progression.
Gene→Variant (gene-first): 1788:V716F
Genes: 1788
Variants: V716F
Next, we determined whether metformin had superior antitumor activity in KRAS-mutated CRC cell lines to those with KRAS wild type through a cell-viability test. As shown in SI Appendix, Fig. S2A, metformin inhibited the
[Paragraph-level] PMCID: PMC7293710 Section: RESULTS PassageIndex: 7
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses how the KRASG12V mutation correlates with increased sensitivity to the antiproliferation therapy of metformin, indicating a predictive relationship between the variant and treatment response. Oncogenic: The KRASG12V mutation is implicated in tumor development as it is mentioned in the context of its effect on cell viability and sensitivity to therapy in colorectal cancer cell lines.
Gene→Variant (gene-first): 3845:G12V
Genes: 3845
Variants: G12V
To analyze the response of KB1(L1363P)P mammary tumors to HRR deficiency-targeted therapy, we performed orthotopic transplantations with spontaneous donor tumors as previously described. To capture the heterogeneity of K
[Paragraph-level] PMCID: PMC7612117 Section: RESULTS PassageIndex: 15
Evidence Type(s): Predictive, Oncogenic, Functional
Justification: Predictive: The passage discusses the response of KB1(L1363P)P mammary tumors to targeted therapies, indicating that these tumors responded significantly better to cisplatin and the PARP inhibitor AZD2461, which correlates the variant with treatment response. Oncogenic: The variant is associated with tumor development and progression, as it is discussed in the context of mammary tumors and their response to therapies, suggesting a role in cancer biology. Functional: The passage describes how the variant affects the ability of tumor cells to induce RAD51 foci in response to gamma-radiation, indicating an alteration in molecular function related to DNA repair mechanisms.
Gene→Variant (gene-first): 7158:L1363P 7158:p.L1363P
Genes: 7158
Variants: L1363P p.L1363P
KB1(L1363P)P mammary tumors respond to cisplatin and PARP inhibition
[Paragraph-level] PMCID: PMC7612117 Section: RESULTS PassageIndex: 14
Evidence Type(s): Predictive
Justification: Predictive: The variant L1363P is associated with a response to cisplatin and PARP inhibition, indicating its correlation with treatment sensitivity.
Gene→Variant (gene-first): 7158:L1363P
Genes: 7158
Variants: L1363P
KB1P mammary tumors are mainly adenocarcinomas, defined by their epithelial nature and solid growth pattern (Fig. 3D; Supplementary Fig. S4B). In contrast, KB1(L1363P)P mammary tumors are predominantly carcinosarcomas wi
[Paragraph-level] PMCID: PMC7612117 Section: RESULTS PassageIndex: 13
Evidence Type(s): Diagnostic, Oncogenic
Justification: Diagnostic: The passage discusses how KB1(L1363P)P mammary tumors are classified as predominantly carcinosarcomas, indicating that the variant is used to define and classify a specific tumor subtype. Oncogenic: The variant L1363P is associated with the development of carcinosarcomas, suggesting that it contributes to tumor progression and development, which aligns with oncogenic behavior.
Gene→Variant (gene-first): 7158:L1363P 7158:p.L1363P
Genes: 7158
Variants: L1363P p.L1363P
KB1(L1363P)P mammary tumors show EMT-like phenotypes and limited genomic instability
[Paragraph-level] PMCID: PMC7612117 Section: RESULTS PassageIndex: 12
Evidence Type(s): Oncogenic
Justification: Oncogenic: The passage indicates that the variant L1363P is associated with mammary tumors exhibiting EMT-like phenotypes, suggesting a role in tumor development or progression.
Gene→Variant (gene-first): 7158:L1363P
Genes: 7158
Variants: L1363P
The embryonic lethality of Brca1LP/LP mice indicates that an intact BRCA1 coiled-coil domain is functionally important in vivo, in line with its requirement for BRCA1-mediated HRR. To analyze whether the functional defec
[Paragraph-level] PMCID: PMC7612117 Section: RESULTS PassageIndex: 11
Evidence Type(s): Oncogenic, Functional
Justification: Oncogenic: The passage discusses how the Brca1 p.L1363P variant contributes to tumor formation and accelerates tumor development in a mouse model, indicating its role in tumor progression. Functional: The passage indicates that the Brca1 p.L1363P variant has a functional defect that compromises BRCA1-mediated homologous recombination repair (HRR), suggesting an alteration in molecular function.
Gene→Variant (gene-first): 7158:L1363P 7158:p.L1363P
Genes: 7158
Variants: L1363P p.L1363P
Brca1 p.L1363P shows a defect in mammary tumor suppression
[Paragraph-level] PMCID: PMC7612117 Section: RESULTS PassageIndex: 10
Evidence Type(s): Oncogenic
Justification: Oncogenic: The variant p.L1363P is associated with a defect in mammary tumor suppression, indicating its contribution to tumor development or progression.
Gene→Variant (gene-first): 7158:p.L1363P
Genes: 7158
Variants: p.L1363P
To verify whether mouse Brca1 p.L1363P phenocopies human BRCA1 p.L1407P, we analyzed Brca1LP/LP;Trp53Delta/Delta (LP/LP) mutant and Brca1LP/+;Trp53Delta/Delta (LP/+) control MEFs for BRCA1-PALB2 interaction and HRR defec
[Paragraph-level] PMCID: PMC7612117 Section: RESULTS PassageIndex: 9
Evidence Type(s): Predictive, Functional
Justification: Predictive: The passage discusses increased sensitivity to cisplatin and PARP1 inhibition in the context of the Brca1 p.L1363P variant, indicating a correlation with treatment response. Functional: The variant p.L1363P is shown to severely attenuate BRCA1-PALB2 binding, which alters the molecular function related to homologous recombination repair (HRR).
Gene→Variant (gene-first): 672:leucine to proline 7158:p.L1363P 672:p.L1407P
Genes: 672 7158
Variants: leucine to proline p.L1363P p.L1407P
BRCA1 p.L1363P is unable to bind PALB2 and shows hypomorphic activity in HRR
[Paragraph-level] PMCID: PMC7612117 Section: RESULTS PassageIndex: 8
Evidence Type(s): Functional
Justification: Functional: The passage indicates that the variant p.L1363P alters the binding ability of BRCA1 to PALB2 and affects its activity in homologous recombination repair (HRR), demonstrating a change in molecular function.
Gene→Variant (gene-first): 7158:p.L1363P
Genes: 7158
Variants: p.L1363P
In the complete absence of TP53, Brca1LP/LP mice developed apparently normal until at least E13.5, although no postnatal survival was observed upon compound heterozygous intercrosses (Table 3). This allowed us to isolate
[Paragraph-level] PMCID: PMC7612117 Section: RESULTS PassageIndex: 7
Evidence Type(s): Functional
Justification: Functional: The passage discusses the evaluation of the functional consequences of the Brca1 p.L1363P variant, indicating that it alters molecular or biochemical function.
Gene→Variant (gene-first): 7158:p.L1363P
Genes: 7158
Variants: p.L1363P
For a first functional analysis of Brca1 p.L1363P in vivo, heterozygous Brca1LP mice were intercrossed and their offspring was genotyped. No Brca1LP/LP mice were born; therefore, embryos were analyzed at different stages
[Paragraph-level] PMCID: PMC7612117 Section: RESULTS PassageIndex: 5
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses a functional analysis of the Brca1 p.L1363P variant, indicating that it alters embryonic development and leads to growth defects in mice, which demonstrates its impact on molecular or biochemical function. Oncogenic: The analysis of the Brca1 p.L1363P variant in the context of embryonic development and its comparison to Brca1-null mice suggests that it may contribute to tumor development or progression, as it is associated with severe phenotypes similar to pathogenic mutations in Brca1.
Gene→Variant (gene-first): 7158:p.L1363P
Genes: 7158
Variants: p.L1363P
Homozygous Brca1 p.L1363P (FVB) mice die during embryonic development
[Paragraph-level] PMCID: PMC7612117 Section: RESULTS PassageIndex: 4
Evidence Type(s): Oncogenic
Justification: Oncogenic: The passage indicates that the homozygous variant p.L1363P in Brca1 leads to embryonic lethality in mice, suggesting that it contributes to tumor development or progression.
Gene→Variant (gene-first): 7158:p.L1363P
Genes: 7158
Variants: p.L1363P
We used CRISPR/Cas9-mediated genome editing in FVB mouse zygotes to model the BRCA1 coiled-coil domain VUS c.4220T>C p.L1407P, which disrupts the interaction of BRCA1 with PALB2. The BRCA1 coiled-coil domain is well cons
[Paragraph-level] PMCID: PMC7612117 Section: RESULTS PassageIndex: 3
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses how the variant p.L1407P disrupts the interaction of BRCA1 with PALB2 and predicts that it disables the alpha-helical structure of the coiled-coil domain, indicating an alteration in molecular function. Oncogenic: The use of CRISPR/Cas9 to model the BRCA1 variant in mice suggests that the variant contributes to tumor development or progression, as it is being studied in the context of a gene essential for embryonic development and cancer biology.
Gene→Variant (gene-first): 672:4220T>C 7158:p.L1363P 672:p.L1407P
Genes: 672 7158
Variants: 4220T>C p.L1363P p.L1407P
Generation of Brca1 p.L1363P (FVB) mice
[Paragraph-level] PMCID: PMC7612117 Section: RESULTS PassageIndex: 2
Evidence Type(s): None
Justification: Not enough information in this passage.
Gene→Variant (gene-first): 7158:p.L1363P
Genes: 7158
Variants: p.L1363P
MIB-1 labeling indices correlated with the diagnosis and grade assigned prior to H3 K27M IHC testing (Table 1). For the adult cohort, 1 case met WHO criteria for diffuse astrocytoma, WHO grade II (MIB-1 < 1%), 7 cases me
[Paragraph-level] PMCID: PMC5822176 Section: RESULTS PassageIndex: 6
Evidence Type(s): Diagnostic
Justification: Diagnostic: The passage discusses the correlation of MIB-1 labeling indices with the diagnosis and grade of tumors, indicating that the K27M variant is associated with specific tumor classifications.
Gene→Variant (gene-first): 3417:K27M
Genes: 3417
Variants: K27M
The known lower frequency of ATRX mutation/loss of ATRX nuclear immunostaining in only 10 - 15% of H3 K27M-mutant tumors makes this feature less amenable to comparisons between the 2 cohorts. However, of the 7 adult case
[Paragraph-level] PMCID: PMC5822176 Section: RESULTS PassageIndex: 5
Evidence Type(s): None
Justification: Not enough information in this passage.
Gene→Variant (gene-first): 3417:K27M
Genes: 3417
Variants: K27M
Four cases had other morphologies at initial biopsy, including pure GG (n = 3, pediatric) and PA (n = 1, adult) histologies. One of the GGs was a 16-year-old girl with an original biopsy demonstrating a pure thalamic GG
[Paragraph-level] PMCID: PMC5822176 Section: RESULTS PassageIndex: 4
Evidence Type(s): Oncogenic
Justification: Oncogenic: The passage discusses the transformation of tumors associated with the K27M variant, indicating its role in tumor development and progression, particularly in the context of glioblastoma transformation.
Gene→Variant (gene-first): 3417:K27M
Genes: 3417
Variants: K27M
Table 1 summarizes the ages, gender, anatomical location, initial histological diagnoses, and p53 IHC labeling indices discerned prior to H3 K27M IHC in the 28 H3 K27M-mutant tumors identified in our databases. There wer
[Paragraph-level] PMCID: PMC5822176 Section: RESULTS PassageIndex: 2
Evidence Type(s): Diagnostic, Oncogenic
Justification: Diagnostic: The passage discusses the identification of H3 K27M-mutant tumors and provides demographic information, indicating that the variant is associated with specific histological diagnoses and patient characteristics. Oncogenic: The mention of H3 K27M in the context of tumors suggests that this somatic variant contributes to tumor development or progression, as it is identified in mutant tumors.
Gene→Variant (gene-first): 3417:K27M
Genes: 3417
Variants: K27M
Background: H3 K27M mutation was originally described in pediatric diffuse intrinsic pontine gliomas (DIPGs), but has been recently recognized to occur also in adult midline diffuse gliomas, as well as midline tumors wit
[Paragraph-level] PMCID: PMC5822176 Section: ABSTRACT PassageIndex: 1
Evidence Type(s): Diagnostic, Prognostic, Oncogenic
Justification: Diagnostic: The passage discusses the H3 K27M mutation's association with various tumor types, indicating its role in defining and classifying these tumors, particularly in pediatric and adult cohorts. Prognostic: The passage mentions survival outcomes for patients with H3 K27M-mutant tumors, comparing mean survival times between adults and pediatric patients, which indicates a correlation with disease outcome. Oncogenic: The H3 K27M mutation is described as contributing to tumor development in various glioma types, indicating its role as a somatic variant involved in tumor progression.
Gene→Variant (gene-first): 3417:K27M
Genes: 3417
Variants: K27M
To identify somatic mutations in paediatric diffuse intrinsic pontine gliomas (DIPGs), we performed whole genome sequencing of 7 DIPGs and matched germline DNA, and targeted sequencing of an additional 43 DIPGs and 36 no
[Paragraph-level] PMCID: PMC3288377 Section: ABSTRACT PassageIndex: 1
Evidence Type(s): Diagnostic, Oncogenic
Justification: Diagnostic: The passage discusses the frequency of the p.K27M mutation in DIPGs and its association with this specific subtype of brain tumors, indicating its role in defining or classifying the disease. Oncogenic: The p.K27M and p.G34R mutations are described as somatic mutations found in pediatric gliomas, suggesting their contribution to tumor development or progression.
Gene→Variant (gene-first): 3021:p.G34R 3021:p.K27M
Genes: 3021
Variants: p.G34R p.K27M
CDK4/6 inhibition with endocrine therapy is now a standard of care for advanced estrogen receptor positive breast cancer. Mechanisms of CDK4/6 inhibitor resistance have been described pre-clinically, with limited evidenc
[Paragraph-level] PMCID: PMC6368247 Section: ABSTRACT PassageIndex: 1
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the emergence of the ESR1 Y537S mutation in the context of resistance to CDK4/6 inhibitors, indicating a correlation with treatment response and resistance. Oncogenic: The mention of the ESR1 Y537S mutation as a new driver mutation suggests that it contributes to tumor development or progression, particularly in the context of breast cancer.
Gene→Variant (gene-first): 5728:Y537S
Genes: 5728
Variants: Y537S
Twenty-seven patients with a median age of 49 years (range 23-82) were treated with BRAF inhibitors. Eleven patients received dabrafenib with trametinib, and 16 were treated with vemurafenib. Patients received 150 mg of
[Paragraph-level] PMCID: PMC5122709 Section: RESULTS PassageIndex: 3
Evidence Type(s): Predictive, Diagnostic, Oncogenic
Justification: Predictive: The passage discusses patients treated with BRAF inhibitors, specifically mentioning the BRAF V600E mutation, which correlates with response to these therapies. Diagnostic: The passage states that all patients tested positive for the BRAF V600E mutation, indicating its use in defining or confirming the presence of a specific subtype of melanoma. Oncogenic: The BRAF V600E mutation is implicated in the development of melanoma, suggesting its role as a somatic variant contributing to tumor progression.
Gene→Variant (gene-first): 673:V600E
Genes: 673
Variants: V600E
Although activating mutations of FGFR3 are frequent in bladder tumors, little information is available on their specific effects in urothelial cells or the basis for the observed mutation spectrum. We investigated the ph
[Paragraph-level] PMCID: PMC2789045 Section: ABSTRACT PassageIndex: 1
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses how the FGFR3 mutations (S249C, Y375C, and K652E) alter molecular signaling pathways, specifically the phosphorylation of various proteins, indicating a change in biochemical function. Oncogenic: The passage describes how the mutant FGFR3 variants induce morphological transformation, cell proliferation, and anchorage-independent growth, which are indicative of their role in tumor development and progression.
Gene→Variant (gene-first): 2261:K652E 2261:S249C 2261:Y375C
Genes: 2261
Variants: K652E S249C Y375C
Mutations in the KRAS oncogene are found in more than 90% of patients with pancreatic ductal adenocarcinoma (PDAC), with Gly-to-Asp mutations (KRASG12D) being the most common. Here, we tested the efficacy of a small-mole
[Paragraph-level] PMCID: PMC9900321 Section: ABSTRACT PassageIndex: 3
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the efficacy of a small-molecule KRASG12D inhibitor, MRTX1133, in treating pancreatic ductal adenocarcinoma, indicating a correlation between the Gly-to-Asp mutation and response to therapy. Oncogenic: The Gly-to-Asp mutation in the KRAS oncogene is described as contributing to tumor development in pancreatic ductal adenocarcinoma, as it is found in more than 90% of patients with this cancer type.
Gene→Variant (gene-first): 3845:Gly-to-Asp
Genes: 3845
Variants: Gly-to-Asp
Macrodactyly is a discrete congenital anomaly consisting of enlargement of all tissues localized to the terminal portions of a limb, typically within a 'nerve territory'. The classic terminology for this condition is 'li
[Paragraph-level] PMCID: PMC3542862 Section: ABSTRACT PassageIndex: 1
Evidence Type(s): Oncogenic, Functional
Justification: Oncogenic: The passage discusses somatic mutations in PIK3CA (including R115P, E542K, H1047L, and H1047R) that contribute to the pathophysiology of macrodactyly, indicating their role in tumor development or progression through activation of the PI3K/AKT signaling pathway. Functional: The passage mentions that the identified mutations lead to AKT activation, which indicates that these variants alter molecular or biochemical function related to cell signaling pathways.
Gene→Variant (gene-first): 5290:E542K 5290:H1047L 5290:H1047R 5163:R115P
Genes: 5290 5163
Variants: E542K H1047L H1047R R115P
Mutations in KRAS and BRAF were associated with inferior PFS and OS of mCRC patients compared with patients with non-mutated tumors. KRAS exon 2 mutation variants were associated with heterogeneous outcome compared with
[Paragraph-level] PMCID: PMC4999563 Section: ABSTRACT PassageIndex: 9
Evidence Type(s): Prognostic, Diagnostic
Justification: Prognostic: The passage indicates that KRAS G12C and G13D mutations are associated with inferior progression-free survival (PFS) and overall survival (OS) in mCRC patients, suggesting a correlation with disease outcome independent of therapy. Diagnostic: The mention of KRAS mutations being associated with heterogeneous outcomes compared to unmutated tumors implies that these variants can be used to classify or define a disease subtype in mCRC.
Gene→Variant (gene-first): 3845:G12C 3845:G13D
Genes: 3845
Variants: G12C G13D