Oncogenic, Functional evidence:

Oncogenic: The abstract indicates that the p.Lys27Met substitution in histone H3 variants is associated with pediatric midline high-grade astrocytomas (mHGAs), suggesting that this somatic variant contributes to tumor development or progression. The mention of specific mutations and their association with tumor location further supports the oncogenic role of this variant in the context of these tumors.

Functional: The study discusses how the p.Lys27Met alteration is linked to hyperactivation of the BMP-ACVR1 pathway and increased levels of phosphorylated SMAD proteins, indicating that this variant alters molecular or biochemical function within the tumor cells. This suggests a functional impact of the variant on the signaling pathways involved in tumor biology.

Oncogenic, Functional evidence:

Oncogenic: The abstract discusses how the p.Lys27Met substitution in histone H3 variants is associated with pediatric midline high-grade astrocytomas (mHGAs) and highlights its role in driving the epigenetic phenotype of these tumors, indicating that this variant contributes to tumor development or progression.

Functional: The study mentions that the p.Lys27Met alteration is associated with hyperactivation of the BMP-ACVR1 developmental pathway and increased levels of phosphorylated SMAD proteins, suggesting that this variant alters molecular or biochemical function in tumor cells.

Diagnostic, Oncogenic evidence:

Diagnostic: The K27M mutation in histone H3.3 is used to define clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas, indicating its role in classifying the disease.

Oncogenic: The mention of the K27M mutation in histone H3.3 suggests that it contributes to tumor development or progression, particularly in the context of pediatric diffuse intrinsic pontine gliomas.

Prognostic, Oncogenic evidence:

Oncogenic: The K27M mutation in histone H3.3 is described as being present in approximately 70% of DIPGs, indicating its significant role in tumor development. The mention of its association with dysregulation of the PRC2 complex and its high frequency in tumors supports its contribution to tumorigenesis.

Prognostic: The study reports that the K27M mutation confers a worse overall survival compared to H3.3 wild-type patients, indicating that this variant is associated with disease outcome independent of therapy. This correlation with survival outcomes classifies it as prognostic evidence.

Prognostic, Oncogenic evidence:

Oncogenic: The K27M mutation in histone H3.3 is described as being present in approximately 70% of DIPGs and is likely relevant for tumorigenesis, indicating its role in cancer development. The mention of its high frequency and association with specific genetic alterations further supports its oncogenic potential.

Prognostic: The study reports that the K27M mutation confers a worse overall survival compared to H3.3 wild-type patients, indicating that this variant is associated with disease outcome independent of therapy. This correlation with survival outcomes classifies it as prognostic evidence.

Diagnostic, Oncogenic evidence:

Diagnostic: The abstract states that nearly 80% of DIPGs harbor a K27M mutation, indicating its association with the disease and suggesting its use as a biomarker for classification.

Oncogenic: The mention of frequent histone 3 mutations (K27M-H3) in DIPG suggests that this somatic variant contributes to tumor development, as it is implicated in the unique genetic landscape of this aggressive brain cancer.

Diagnostic, Oncogenic evidence:

Diagnostic: The abstract states that nearly 80% of DIPGs harbor a K27M mutation, indicating its association with the disease and suggesting its use as a biomarker for classification.

Oncogenic: The mention of frequent histone 3 mutations (K27M-H3) in DIPG suggests that this somatic variant contributes to tumor development, as it is implicated in the unique genetic makeup of this aggressive brain cancer.

nan evidence:

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nan evidence:

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Diagnostic, Functional evidence:

Diagnostic: The abstract states that the glycine-to-arginine alteration at codon 34 (G34R) within H3F3A occurs exclusively in pediatric glioblastomas, indicating its use in defining or classifying a specific disease subtype. The mention of the mutation's presence in a certain percentage of glioma cases further supports its role as a diagnostic marker.

Functional: The study investigates alterations in histone methylation in G34R-mutant samples, suggesting that this variant affects molecular functions related to histone modification. This indicates that the G34R mutation alters biochemical processes within the tumor cells.

Diagnostic, Functional evidence:

Diagnostic: The abstract states that the glycine-to-arginine alteration at codon 34 (G34R) within H3F3A occurs exclusively in pediatric glioblastomas, indicating its use in defining or classifying a specific disease subtype. The mention of the mutation's presence in tumor samples from patients further supports its diagnostic relevance.

Functional: The study investigates alterations in histone methylation in G34R-mutant samples, suggesting that this variant affects molecular functions related to histone modification. The analysis of histone methylation patterns indicates that the G34R mutation may alter biochemical functions within the tumor context.

Diagnostic, Prognostic evidence:

Diagnostic: The study suggests that the presence of the H3.3 G34 mutation should be recommended as a routine diagnostic marker for supratentorial CNS tumors across a broad histological spectrum, indicating its role in defining and classifying these tumors.

Prognostic: The survival analysis identified the presence of amplified oncogene(s) and MGMT methylation as independent prognostic markers for poor and favorable outcomes, respectively, indicating that the H3 G34 mutation may correlate with disease outcomes.

Diagnostic, Prognostic evidence:

Diagnostic: The study suggests that the H3.3 G34 mutation should be recommended as a routine diagnostic marker for supratentorial CNS tumors across a broad histological spectrum, indicating its role in defining and classifying these tumors.

Prognostic: The survival analysis identified the presence of amplified oncogene(s) and MGMT methylation as independent prognostic markers for poor and favorable outcomes, respectively, indicating that the H3 G34 mutation may correlate with disease outcomes.

Diagnostic, Oncogenic evidence:

Diagnostic: The abstract states that "each H3F3A mutation defines an epigenetic subgroup of GBM with a distinct global methylation pattern," indicating that these mutations are used to classify and define specific subtypes of glioblastoma.

Oncogenic: The abstract mentions that the H3F3A mutations "give rise to GBMs in separate anatomic compartments," suggesting that these somatic mutations contribute to tumor development and progression in glioblastoma.

Diagnostic, Oncogenic evidence:

Diagnostic: The study identifies recurrent H3F3A mutations that define distinct epigenetic subgroups of glioblastoma (GBM), indicating that these mutations are used to classify the disease into specific subtypes based on their unique methylation patterns.

Oncogenic: The H3F3A mutations are implicated in the development of GBMs, as the study demonstrates that these mutations contribute to tumor formation in separate anatomic compartments, suggesting their role in tumor progression.

Diagnostic, Oncogenic evidence:

Diagnostic: The study identifies recurrent H3F3A mutations that define distinct epigenetic subgroups of glioblastoma (GBM), indicating that these mutations are used to classify the disease into specific subtypes based on their unique methylation patterns.

Oncogenic: The H3F3A mutations are implicated in the development of GBMs, as the study demonstrates that these mutations contribute to tumor formation in separate anatomic compartments, suggesting a role in tumor progression.

Diagnostic, Prognostic evidence:

Diagnostic: The abstract 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. This suggests that the variant is used to confirm or classify a disease subtype.

Prognostic: The results indicate that patients with H3 K27M-mutant tumors have a poor prognosis, with mean survival times reported for both adults and children. This correlation with adverse outcomes, independent of therapy, supports the classification as prognostic evidence.

nan evidence:

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nan evidence:

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Diagnostic, Oncogenic evidence:

Oncogenic: The BRAF:p.V600E mutation is mentioned as being present in a proportion of low-grade glioneuronal tumors (LGGNTs), indicating its role in tumor development or progression, which aligns with the definition of an oncogenic variant.

Diagnostic: The abstract discusses the presence of the BRAF:p.V600E mutation in sporadic cerebellar pilocytic astrocytomas and its association with the activation of the MAPK/ERK pathway, suggesting its use as a biomarker for classifying these tumors.

Diagnostic, Prognostic evidence:

Diagnostic: The study discusses how pediatric low-grade gliomas (pLGG) can be classified based on their alteration type, indicating that these genetic alterations are used to define and categorize the disease, which aligns with the definition of diagnostic evidence.

Prognostic: The abstract mentions that rearrangement-driven tumors infrequently progressed and rarely resulted in death compared to SNV-driven tumors, suggesting that the type of genetic alteration correlates with disease outcomes, which is indicative of prognostic evidence.

Diagnostic, Prognostic evidence:

Diagnostic: The study discusses how pediatric low-grade gliomas (pLGG) can be classified based on their alteration type, indicating that these genetic alterations are used to define and categorize the disease. The mention of different clinical-molecular correlates further supports the use of these variants in diagnosing and stratifying pLGG subtypes.

Prognostic: The abstract notes that rearrangement-driven tumors are diagnosed at a younger age, infrequently progress, and rarely result in death compared to SNV-driven tumors, suggesting that these variants correlate with disease outcomes independent of therapy. This classification into risk categories indicates a prognostic value associated with the different alteration types in pLGG.

Diagnostic, Prognostic evidence:

Diagnostic: The study discusses how pediatric low-grade gliomas (pLGG) can be classified based on their alteration type, indicating that these genetic alterations are used to define and classify the disease and its subtypes. The mention of clinical-molecular correlates further supports the use of these variants in diagnosing and stratifying pLGG into risk categories.

Prognostic: The abstract notes that rearrangement-driven tumors infrequently progressed and rarely resulted in death compared to SNV-driven tumors, suggesting that the type of genetic alteration correlates with disease outcomes independent of therapy. This indicates a prognostic relationship between the variant types and clinical outcomes in pLGG.

Diagnostic, Prognostic evidence:

Diagnostic: The study discusses how pediatric low-grade gliomas (pLGG) can be classified based on their alteration type, indicating that these genetic alterations are used to define and classify the disease and its subtypes. The mention of "broadly classified based on their alteration type" supports the use of these variants in diagnosing and categorizing the tumors.

Prognostic: The abstract notes that rearrangement-driven tumors "infrequently progressed, and rarely resulted in death" compared to SNV-driven tumors, suggesting that the presence of specific variants correlates with disease outcomes independent of therapy. This indicates a prognostic value of the variants in predicting clinical outcomes for patients with pLGG.

Diagnostic, Oncogenic evidence:

Diagnostic: The study discusses the frequency of the BRAF p.V600E variant in various types of glial tumors, indicating its association with specific tumor subtypes, which supports its use as a biomarker for diagnosis and classification of these tumors.

Oncogenic: The presence of the BRAF p.V600E variant is noted in multiple tumor types, suggesting its role in tumor development and progression, which aligns with the definition of an oncogenic variant.

Predictive, Oncogenic evidence:

Predictive: The abstract discusses the patient's response to combination targeted therapy with a selective BRAF inhibitor (dabrafenib) and MEK inhibitor (trametinib), indicating that the presence of the BRAF p.T599dup mutation is associated with a positive clinical response to this treatment regimen.

Oncogenic: The mention of the BRAF p.T599dup mutation in the context of a ganglioglioma suggests that this somatic variant contributes to tumor development or progression, as it is associated with a specific tumor type and treatment response.

Predictive, Oncogenic evidence:

Predictive: The abstract mentions that midostaurin has been approved for KIT D816V-positive systemic mastocytosis, indicating that this variant correlates with a specific therapy, demonstrating its predictive value in treatment response.

Oncogenic: The abstract discusses the presence of the KIT D816V mutation in the context of oncogenic receptor tyrosine kinases, suggesting that this somatic variant contributes to tumor development or progression, which aligns with the definition of oncogenic evidence.

Predictive, Oncogenic evidence:

Oncogenic: The BRAFG469V mutation was identified as the only known oncogenic mutation in the patient-derived xenograft model, indicating its role in tumor development. Additionally, the study confirmed that small interfering RNA knockdown of BRAF, but not EGFR, resulted in cell death, further supporting BRAFG469V as an oncogenic driver.

Predictive: The study demonstrated that the BRAFG469V mutation is sensitive to multiple EGFR tyrosine kinase inhibitors (TKIs), suggesting that this variant correlates with response to therapy. The findings indicate that clinically approved EGFR TKIs can be repurposed for treating patients with lung cancer harboring the BRAFG469V mutation.

Predictive, Prognostic evidence:

Prognostic: The study mentions that FLT3 mutations, including point mutations within the tyrosine kinase domain, are associated with short relapse-free and overall survival, indicating a correlation between these mutations and disease outcomes.

Predictive: The abstract discusses the transient clinical responses to FLT3 kinase inhibitors and the high rates of relapse and drug resistance, suggesting that the presence of specific mutations, such as those in the tyrosine kinase domain, can influence treatment response and resistance to therapy.

Diagnostic, Oncogenic, Functional evidence:

Functional: The study reports that the C124S variant is "both protein- and lipid-phosphatase catalytically inactive," indicating that it alters the molecular function of the PTEN protein. This suggests a direct impact on the biochemical activity of the protein, which is a key aspect of functional evidence.

Diagnostic: The abstract mentions that mutations in PTEN, including C124S, have been associated with various human diseases, including autism spectrum disorder and cancer. This association implies that the variant can be used to classify or define these diseases, supporting its classification as diagnostic.

Oncogenic: The results indicate that C124S has been found in somatic cancer, suggesting that this variant contributes to tumor development or progression. This aligns with the oncogenic evidence type, as it demonstrates a direct link between the variant and cancer.

Predictive, Diagnostic evidence:

Predictive: The study discusses FGFR1 amplification (FGFR1amp) as being associated with resistance to endocrine therapy and CDK4/6 inhibitors, indicating that the variant correlates with treatment response. Additionally, it mentions that high FGFR1-4 mRNA levels are associated with FGFRi response, further supporting its predictive nature regarding therapy outcomes.

Diagnostic: FGFR1 amplification is described as recurrent in metastatic breast cancer (MBC) and is used to identify responders to FGFR inhibitors and multi-tyrosine kinase inhibitors, indicating its role in classifying and defining a specific subtype of breast cancer. This association with a specific disease context supports its classification as a diagnostic evidence type.

Oncogenic, Functional evidence:

Functional: The study provides evidence that the BRCA1 missense variant p.L1363P disrupts the interaction with PALB2, leading to defects in homologous recombination repair (HRR) and increased sensitivity to DNA-damaging agents, indicating an alteration in molecular function.

Oncogenic: The results demonstrate that the Brca1 p.L1363P variant accelerates the development of mammary tumors in a mouse model, suggesting that this somatic variant contributes to tumor development and progression.

Predictive, Diagnostic, Prognostic evidence:

Predictive: The study discusses how the presence of the EML4-ALK fusion variant 3 and TP53 mutation in plasma were associated with poor progression-free survival (PFS), indicating that these variants may correlate with treatment response to brigatinib versus crizotinib.

Prognostic: The results mention that the median overall survival was not reached in either treatment group, but there was a suggested survival benefit for brigatinib in patients with baseline brain metastases, indicating a correlation with disease outcome independent of therapy.

Diagnostic: The presence of the EML4-ALK fusion variant 3 is used to assess clinical efficacy and is associated with poor PFS, suggesting its role in defining or classifying the disease in the context of treatment response.

Predictive evidence:

Predictive: The abstract indicates that adavosertib improved progression-free survival (PFS) in patients with RAS/TP53-mutant metastatic colorectal cancer (mCRC), suggesting a correlation between the RAS/TP53 mutations and response to this specific therapy. This aligns with the definition of predictive evidence, as it discusses treatment response in relation to the variant.

Oncogenic, Functional evidence:

Functional: The study discusses how mutations in the N-terminal region of PTEN, including Lys13, affect its PIP3 phosphatase activity and nuclear localization, indicating that these variants alter the molecular function of PTEN. The mention of monoubiquitylation of Lys13 being required for PTEN nuclear entry further supports this classification.

Oncogenic: The abstract and results highlight the role of PTEN as a tumor suppressor and its involvement in tumor progression when its nuclear localization is lost, suggesting that mutations in this region, including those at position 13, contribute to tumor development or progression. The association of PTEN's functions with cancer outcomes reinforces its oncogenic relevance.

Functional evidence:

Functional: The study discusses the D92N mutation and its partial activity, indicating that this variant alters the biochemical function of the PTEN protein, specifically its phosphatase activity. The mention of the mutation's impact on PTEN function supports its classification as a functional variant.

Prognostic evidence:

Prognostic: The study reports that high-grade mucinous adenocarcinoma (high-MC) is significantly associated with shorter disease-free survival (DFS) and overall survival (OS) periods compared to low-grade mucinous adenocarcinoma (low-MC) and nonmucinous carcinoma, indicating that high-MC serves as an independent prognostic factor in colorectal cancer (CRC).

Predictive, Oncogenic evidence:

Predictive: The study discusses the efficacy of onvansertib, a PLK1 inhibitor, in inhibiting tumor growth in Group 3 medulloblastoma, indicating its potential as a therapeutic strategy. The mention of "tumor growth inhibition" and "IC50 concentrations" suggests a correlation with treatment response, which aligns with predictive evidence.

Oncogenic: The abstract states that PLK1 is an "oncogenic kinase" and is overexpressed in Group 3 medulloblastoma, indicating its role in tumor development and progression. This supports the classification of the variant as oncogenic due to its contribution to cancer biology.

Predictive evidence:

Predictive: The study demonstrates a correlation between SNAI2 expression levels and radiosensitivity, indicating that SNAI2 could potentially predict clinical responses to ionizing radiation treatment in rhabdomyosarcoma. This suggests that modulation of SNAI2 levels may influence treatment outcomes, aligning with the predictive evidence type.

Predictive, Functional evidence:

Predictive: The study identifies somatic missense mutations in the ERCC2 gene as being associated with improved response to cisplatin-based chemotherapy in muscle-invasive bladder cancer (MIBC), indicating that these mutations can serve as predictive biomarkers for treatment response.

Functional: The research demonstrates that introducing an ERCC2 mutation into a bladder cancer cell line abrogates nucleotide excision repair (NER) activity, highlighting the functional impact of these mutations on molecular processes related to cisplatin sensitivity.

Predictive, Oncogenic evidence:

Predictive: The study discusses how treatment with KRAS G12C inhibitors, such as sotorasib, can lead to substantial tumor regression in patients with non-small cell lung cancer (NSCLC), indicating a correlation between the G12C variant and response to therapy. Additionally, the exploration of dual blockade of MET and KRAS G12C as a treatment option suggests that the variant's presence influences treatment strategies.

Oncogenic: The presence of the KRAS G12C variant is implicated in the development of resistance mechanisms in NSCLC, as the study identifies subclonal evolution and MET amplification in KRAS G12C NSCLC cells that have developed resistance, indicating that this variant contributes to tumor progression. The mention of tumor shrinkage in xenograft models further supports the oncogenic role of the G12C variant.

Predictive evidence:

Predictive: The study discusses the efficacy of the erlotinib plus bevacizumab regimen in patients with advanced non-small cell lung cancer (NSCLC), specifically noting that progression-free survival (PFS) was significantly improved in patients with untreated metastatic EGFR-mutated NSCLC. This indicates a correlation between the EGFR mutation and response to the combined therapy, classifying it as predictive evidence.

Predictive, Oncogenic evidence:

Oncogenic: The abstract states that the G63R mutation, along with other EGFR mutants, is oncogenic and able to transform cells in a ligand-independent manner, indicating its role in tumor development.

Predictive: The abstract mentions that a subset of EGFR mutations, including G63R, can serve as genomic predictors for response to anti-EGFR antibodies, suggesting that this variant correlates with treatment response.

Predictive, Oncogenic evidence:

Predictive: The study discusses the anticancer activity of sotorasib in patients with KRAS p.G12C-mutated advanced solid tumors, indicating a correlation between the presence of this variant and the response to therapy. The mention of "objective response" and "response to sotorasib therapy" supports this classification.

Oncogenic: The variant p.G12C is implicated in the context of advanced non-small-cell lung cancer (NSCLC), suggesting that it contributes to tumor development or progression. The study focuses on patients with this specific mutation, which is known to drive oncogenic processes in cancer.

Predictive, Oncogenic evidence:

Predictive: The study discusses the anticancer activity of sotorasib in patients with KRAS p.G12C-mutated advanced solid tumors, indicating a correlation between the presence of this variant and the response to therapy. The mention of "objective response" and "response to sotorasib therapy" supports this classification.

Oncogenic: The variant p.G12C is implicated in the context of advanced non-small-cell lung cancer (NSCLC), suggesting that it contributes to tumor development or progression, which aligns with the definition of an oncogenic variant. The study focuses on the specific mutation in relation to cancer treatment, reinforcing its role in oncogenesis.

Oncogenic evidence:

Oncogenic: The study demonstrates that the NFASC-NTRK1 fusion gene contributes to tumor formation in glioblastoma multiforme, as evidenced by increased proliferation, colony formation, and tumor formation in vivo, indicating its role in tumor development or progression.

Diagnostic, Oncogenic evidence:

Diagnostic: The abstract mentions that mutations in JAK2V617F co-occur with other oncogenic mutations in hematological malignancies, indicating its role in defining or classifying a disease subtype. This suggests that the presence of JAK2V617F is associated with specific malignancies, supporting its use as a diagnostic marker.

Oncogenic: The variant JAK2V617F is described in the context of co-occurring with other oncogenic mutations, implying its contribution to tumor development or progression in hematological malignancies. This association with oncogenic tyrosine kinases indicates that JAK2V617F plays a role in the pathogenesis of these cancers.

Predictive evidence:

Predictive: The study found that mutations in the TP53 gene, particularly those affecting loop domains L2 or L3 of the p53 protein, were associated with a lack of response to chemotherapy, indicating that these mutations may predict resistance to specific treatment regimens in breast cancer.

Predictive, Prognostic evidence:

Predictive: The study indicates that TP53 mutations, particularly those affecting the L2 or L3 domains, are associated with a lack of response to doxorubicin chemotherapy, suggesting that these mutations can predict resistance to this specific treatment. The statistical significance of the association (P = 0.008 for mutations affecting L2/L3) further supports this predictive evidence.

Prognostic: The findings also show that TP53 mutations, along with histological grade and bcl-2 expression, predict relapse-free and breast cancer-specific survival, indicating that these mutations correlate with disease outcomes independent of therapy. The statistical significance of the associations (Ps between <0.0001 and 0.0155) reinforces the prognostic value of TP53 mutations in this context.

Diagnostic, Predisposing evidence:

Predisposing: The study discusses germline mutations in the PTEN gene associated with PTEN hamartoma tumour syndrome (PHTS), which confers an inherited risk for developing various cancers, including breast and thyroid cancers. The mention of "germline mutations" indicates that the variant is inherited, thus fitting the predisposing category.

Diagnostic: The abstract states that PTEN mutations are used to define and classify PHTS, which encompasses several clinical syndromes. This indicates that the variant is associated with a specific disease, fulfilling the criteria for diagnostic evidence.

Diagnostic evidence:

Diagnostic: The variant p.Cys211X is mentioned in the context of tumor samples and is associated with specific histologic types and grades, indicating its role in defining or classifying a disease subtype. This aligns with the use of variants as biomarkers for diagnosis.

Diagnostic, Predisposing evidence:

Diagnostic: The study discusses PTEN germline mutations in the context of PTEN hamartoma tumor syndromes (PHTS), indicating that these mutations are used to classify and confirm the diagnosis of conditions like Bannayan-Riley-Ruvalcaba syndrome and other related syndromes. The mention of PTEN testing in children with specific phenotypic features further supports its role as a diagnostic marker.

Predisposing: The abstract specifies that the PTEN mutation is a germline mutation, which confers inherited risk for developing PHTS, including Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome. This aligns with the definition of predisposing evidence, as it highlights the inherited nature of the mutation and its association with disease risk.

Functional evidence:

Functional: The study discusses how mutations at residues K13 and K289 alter the molecular function of PTEN by affecting its stability and localization, specifically through mechanisms of mono- and polyubiquitination. This indicates that the variant K13 directly influences the biochemical properties of the PTEN protein.

Predictive, Oncogenic evidence:

Predictive: The study discusses how mTORC1 pathway-activating mutations correlate with an exceptional response to treatment with rapalogs, indicating that these mutations can predict sensitivity to this specific therapy in certain cancer types.

Oncogenic: The abstract mentions that mTOR mutations enhance mTORC1 kinase activity and contribute to tumor growth in VHL-deficient cells, demonstrating that these somatic mutations play a role in tumor development and progression.

Predictive, Oncogenic evidence:

Oncogenic: The study provides evidence that the somatic mutation c.7280T>C (p.Leu2427Pro) in the MTOR gene contributes to tumor development and progression, as it induces hyperactivation of the mTOR kinase, which disrupts neuronal migration and leads to spontaneous seizures. This indicates that the variant plays a role in the pathogenesis of focal cortical dysplasia type II (FCDII).

Predictive: The findings suggest that inhibition of mTOR with rapamycin can suppress cytomegalic neurons and epileptic seizures, indicating that the variant may correlate with treatment response in patients with FCDII. This positions the mutation as a potential therapeutic target for managing intractable epilepsy associated with this condition.

Predictive, Oncogenic, Functional evidence:

Functional: The study discusses how mutations in the p53 gene alter its transactivation function, indicating that these variants can change molecular activity and gene regulation. The assessment of p53 mutants' ability to transactivate from various response elements demonstrates a direct link between the mutations and their functional consequences.

Oncogenic: The abstract mentions that mutations in p53, a tumor suppressor, could lead to dramatic phenotypic changes and diversification of cell responses to stress, suggesting that these somatic mutations contribute to tumor development and progression. The classification of p53 mutants as loss of function or retaining transactivation further supports their role in cancer biology.

Predictive: The findings imply that the functionality of specific p53 mutations could affect clinical behavior and outcome in the context of a neoadjuvant chemotherapy treatment trial, indicating a potential correlation between these variants and treatment response.

Predictive, Oncogenic evidence:

Predictive: The study discusses the L1196M mutation as a gatekeeper mutation that limits the durability of response to crizotinib and other ALK inhibitors, indicating its role in resistance to therapy. This suggests that the presence of the L1196M variant correlates with treatment resistance, which is a key aspect of predictive evidence.

Oncogenic: The abstract mentions that the L1196M mutation is a major resistance mechanism to ALK inhibitors, which implies that it contributes to tumor progression and development in the context of ALK+ NSCLC. This aligns with the definition of oncogenic evidence, as the mutation is associated with the cancer-driving behavior of ALK fusion proteins.

Predictive, Oncogenic evidence:

Predictive: The study discusses the potential role of the SHP2 inhibitor SHP099 in combination with molecular-targeted therapy, indicating that this combination may enhance treatment response in ALK/ROS1/EGFR-altered non-small cell lung cancer (NSCLC). The mention of "growth inhibition of cancer cells" suggests a correlation with treatment sensitivity, which aligns with predictive evidence.

Oncogenic: The abstract highlights the involvement of oncogene alterations in ALK/ROS1/EGFR in non-small cell lung cancer, suggesting that these variants contribute to tumor development or progression. The context of resistance to therapies targeting these oncogenes further supports the classification as oncogenic.

Predictive evidence:

Predictive: The study indicates that the combination of mirvetuximab soravtansine and bevacizumab may benefit women with recurrent ovarian cancer and high folate receptor alpha (FRalpha) expression, suggesting a correlation with treatment response. The mention of an objective response rate of 64% in patients with FRalpha-high tumors further supports this predictive evidence.

Predictive, Oncogenic evidence:

Predictive: The presence of the D835Y variant is discussed in the context of a patient receiving an experimental clinical trial with a FLT3 inhibitor, indicating a correlation with treatment response. The mention of achieving complete morphological remission suggests that the variant may influence sensitivity to the therapy.

Oncogenic: The D835Y variant is described as part of two small TKD mutated clones that were detected in the patient, indicating its potential role in tumor development or progression. The presence of this variant alongside the FLT3 ITD mutation suggests it may contribute to the malignancy in the context of Acute Myeloid Leukemia.

Oncogenic evidence:

Oncogenic: The study demonstrates that loss of STAG2 enhances the metastatic potential of Ewing sarcoma xenografts, indicating that STAG2 mutations contribute to tumor development and progression. This is further supported by the observation that the oncogenic genetic program driven by the fusion transcription factor EWS/FLI1 is highly perturbed in STAG2 knockout cells.

Prognostic, Functional evidence:

Prognostic: The study reports that atypical RAS mutations, including KRAS L19F, are associated with worse overall survival in metastatic colorectal cancer (mCRC) compared to RAS/BRAF wild-type, indicating a correlation with disease outcome independent of therapy.

Functional: The study functionally characterized the KRAS L19F variant using in vitro assays, demonstrating that it has varying signaling activity compared to wild-type, which indicates that it alters molecular function.

Predictive, Diagnostic evidence:

Predictive: The study assesses the antitumor activity of pralsetinib, a selective RET inhibitor, in patients with RET fusion-positive NSCLC, indicating a correlation between the RET fusion variant and response to this specific therapy. The mention of overall response rates in patients receiving pralsetinib further supports the predictive nature of the variant in relation to treatment efficacy.

Diagnostic: The paper discusses RET fusion-positive NSCLC, indicating that the presence of the RET fusion variant is used to classify patients with this specific subtype of lung cancer. This classification is essential for determining eligibility for treatment with pralsetinib, thus highlighting the diagnostic role of the variant.

Oncogenic evidence:

Oncogenic: The study identifies the p.G34R mutation in H3F3A as a somatic mutation found in non-brainstem paediatric glioblastomas, indicating its potential role in tumor development or progression. The context of the study focuses on somatic mutations in pediatric diffuse intrinsic pontine gliomas, which supports the classification of this variant as oncogenic.

Diagnostic, Prognostic evidence:

Diagnostic: The study identifies BRAF V600E mutations as a biomarker in pediatric low-grade gliomas (PLGGs), indicating its role in classifying and stratifying these tumors into different risk groups based on their molecular characteristics.

Prognostic: The results show that BRAF V600E is associated with shorter progression-free survival (PFS) and overall survival (OS) in a subset of PLGGs, suggesting its significance in predicting disease outcomes.

Predictive, Prognostic, Oncogenic evidence:

Predictive: The study found that patients with MET amplification were resistant to immune checkpoint blockade (ICB) treatment, indicating a correlation between the MET variant and treatment response. This suggests that MET amplification can predict resistance to ICB therapy, which is crucial for tailoring treatment strategies.

Prognostic: The results indicated that patients with MET amplification had poor progression-free survival, demonstrating that this variant correlates with disease outcome independent of therapy. This highlights the potential of MET amplification as a prognostic marker in lung cancer.

Oncogenic: The study describes how oncogenic MET signaling contributes to tumor behavior by inducing phosphorylation of UPF1 and downregulating STING expression, which is indicative of its role in tumor development and progression. This evidence supports the classification of MET amplification as an oncogenic variant.

Predictive, Oncogenic evidence:

Predictive: The study discusses the therapeutic implications of KRAS mutations, particularly how MEK inhibition has minimal effect as a single agent for PDAC, indicating a relationship between the variant and treatment response. The combination of glucose metabolism inhibition and MEK inhibition shows potential for inducing apoptosis and prolonging overall survival, suggesting that KRAS mutations may influence sensitivity to this combined therapy.

Oncogenic: The abstract highlights the role of KRAS mutations, specifically KrasG12D, in tumor maintenance and progression in pancreatic ductal adenocarcinoma (PDAC), indicating that this somatic variant contributes to tumor development. The investigation into the pathways activated by KRAS mutations further supports its oncogenic role in PDAC.

Diagnostic, Functional evidence:

Diagnostic: The study identifies the presence of MAP2K1 (p.K57N) variants in the tissue adjacent to cartilage, indicating an association with the condition of arteriovenous malformation (AVM). This suggests that the variant is used to classify or confirm the disease state in the affected tissues.

Functional: The presence of the MAP2K1 (p.K57N) variant is shown to have different mutant allele frequencies in endothelial cells compared to non-endothelial cells, indicating that it alters the molecular or biochemical function within these cell types. This suggests a functional impact of the variant on the cellular behavior in the context of AVM.

Predictive, Oncogenic evidence:

Predictive: The study indicates that "depletion of SAMMSON sensitized mutant BRAF melanoma cells to RAF inhibitors in vitro and in vivo," suggesting that SAMMSON plays a role in the response of these cells to therapy, specifically RAF inhibitors. This aligns with the definition of predictive evidence, as it discusses the correlation between the variant and treatment sensitivity.

Oncogenic: The abstract states that "the long noncoding RNA (lncRNA) SAMMSON is required for human melanoma cell growth and survival," indicating that SAMMSON contributes to tumor development or progression in melanoma. This supports the classification as oncogenic, as it highlights the role of SAMMSON in cancer cell viability.

nan evidence:

There are no mentions of the variant in the abstract or results section that provide evidence for any of the CIViC evidence types. Therefore, no classifications can be made based on the provided text.

Predictive, Diagnostic evidence:

Predictive: The study discusses how pembrolizumab improved overall survival (OS) in patients with advanced NSCLC with PD-L1 tumor proportion score (TPS) >=50% and >=1%, indicating a correlation between the PD-L1 status and response to therapy. The hazard ratios provided for OS further support the predictive nature of the variant in relation to treatment outcomes.

Diagnostic: The mention of PD-L1 TPS as a criterion for patient selection in the study indicates its role in classifying patients for treatment, thus serving as a diagnostic marker for advanced NSCLC. The use of specific TPS thresholds to define patient eligibility for pembrolizumab treatment highlights its diagnostic significance.

Predictive, Oncogenic evidence:

Predictive: The study indicates that increased levels of DLL1 in the tumor microenvironment sensitize tumors to anti-CTLA4 treatment, resulting in tumor regression and prolonged survival, which suggests a correlation between DLL1 levels and response to therapy.

Oncogenic: The findings demonstrate that elevated DLL1 levels contribute to tumor vascular normalization and tumor growth inhibition, indicating a role in tumor development or progression within the context of the study.

Predictive, Diagnostic evidence:

Predictive: The study discusses the efficacy of apatinib plus gefitinib as first-line therapy in patients with EGFR-mutant NSCLC, specifically mentioning the L858R mutation as part of the inclusion criteria for treatment-naive patients. This indicates a correlation between the presence of the L858R variant and the response to the combination therapy, thus classifying it as predictive evidence.

Diagnostic: The abstract explicitly states that patients with the EGFR exon 21 L858R mutation were included in the study, indicating that this variant is used to classify and define a specific subtype of NSCLC. This supports the classification of the L858R variant as diagnostic evidence.

Oncogenic, Functional evidence:

Oncogenic: The study identifies the p.Tyr562Cys variant as a somatic variant that contributes to tumor development or progression, specifically in the context of fusiform cerebral aneurysms, as indicated by the presence of somatic-activating PDGFRB variants and their association with overactive auto-phosphorylation and downstream signaling activation.

Functional: The variant is shown to cause non-ligand-dependent auto-phosphorylation in PDGFRB, indicating that it alters the molecular function of the protein, which is supported by the findings of overactive phosphorylation and downstream activation of signaling pathways in patient cells harboring the variant.

Diagnostic, Oncogenic evidence:

Diagnostic: The abstract states that the mosaic PDGFRB c.1685A > G p.(Tyr562Cys) variant is associated with a specific phenotype, indicating its role in defining and classifying conditions related to PDGFRB-activating variants.

Oncogenic: The mention of segmental overgrowth and aneurysms due to the mosaic PDGFRB p.(Tyr562Cys) variant in the results suggests that this somatic variant contributes to tumor development or progression, particularly in the context of vascular malformations.

Oncogenic evidence:

Oncogenic: The study identifies that most vascular anomalies with overgrowth harbor postzygotic gain-of-function mutations in oncogenes, indicating that these somatic variants contribute to tumor development or progression. This is supported by the use of tumor genetic profiling to detect these variants, which are typically associated with cancer.

Oncogenic evidence:

Oncogenic: The study identifies that most vascular anomalies with overgrowth harbor postzygotic gain-of-function mutations in oncogenes, indicating that these somatic variants contribute to tumor development or progression. This is supported by the use of tumor genetic profiling to detect these variants, which are typically associated with cancer.

Oncogenic evidence:

Oncogenic: The study identifies that most vascular anomalies with overgrowth harbor postzygotic gain-of-function mutations in oncogenes, indicating that these somatic variants contribute to tumor development or progression. This is supported by the use of tumor genetic profiling to detect these variants, which are typically associated with cancer.

Oncogenic evidence:

Oncogenic: The study identifies that most vascular anomalies with overgrowth harbor postzygotic gain-of-function mutations in oncogenes, indicating that these somatic variants contribute to tumor development or progression. This is supported by the use of tumor genetic profiling to detect these variants, which are typically associated with cancer.

Diagnostic, Predisposing evidence:

Predisposing: The abstract clearly states that "germline mutations in RASA1 are associated with capillary malformation-arteriovenous malformation (CM-AVM) syndrome," indicating that the c.1248T>G variant is inherited and confers risk for developing this syndrome.

Diagnostic: The mention of the c.1248T>G variant being tracked through the family and identified as a "familial germline heterozygous novel pathogenic RASA1 variant" supports its role in defining and confirming the diagnosis of CM-AVM syndrome.

Diagnostic, Predisposing evidence:

Diagnostic: The study identifies RASA1 mutations as the cause of capillary malformation-arteriovenous malformation (CM-AVM), indicating that these mutations are used to define and confirm the clinical diagnosis of the disorder. The mention of screening RASA1 in patients with specific phenotypes further supports its role as a diagnostic marker for CM-AVM.

Predisposing: The abstract describes CM-AVM as an autosomal-dominant disorder caused by heterozygous RASA1 mutations, which implies that these mutations confer inherited risk for developing the disease. The classification of the disorder as autosomal-dominant suggests a germline origin of the RASA1 mutations involved.

Diagnostic, Oncogenic evidence:

Diagnostic: The study discusses RASA1-related disorders and highlights that variants in the RASA1 gene are associated with hereditary capillary malformations and other vascular malformation syndromes, indicating the use of these variants to classify and confirm the disease.

Oncogenic: The mention of deleterious RASA1 variants contributing to the clinical features of vascular malformation syndromes suggests that these somatic variants may play a role in tumor development or progression, particularly in the context of vascular anomalies.

Diagnostic, Oncogenic evidence:

Diagnostic: The study discusses the association of RASA1 mutations with capillary malformation (CM) and related vascular anomalies, indicating that these mutations can be used to classify and confirm the presence of CM-AVM. The mention of "familial segregation of CM" and the identification of a genetic locus further supports its role in disease classification.

Oncogenic: The abstract describes how heterozygous inactivating RASA1 mutations contribute to the development of atypical capillary malformations and associated vascular anomalies, suggesting a role in tumor development or progression. The involvement of p120-RasGAP in signaling pathways that control cell proliferation and survival indicates its potential oncogenic function.

Diagnostic, Oncogenic, Functional evidence:

Diagnostic: The study presents evidence that a germline mutation involving codon 600 of BRAF is associated with the development of cardio-facio-cutaneous (CFC) syndrome, indicating its role in defining a specific disease phenotype.

Oncogenic: The abstract discusses the somatic mutation p.V600E as frequently found in various tumors, suggesting that mutations at codon 600, including p.V600G, contribute to tumor development or progression, particularly in the context of cancer-associated mutations.

Functional: The in vitro analysis demonstrates that the p.V600G mutation alters the molecular function of BRAF by increasing ERK and ELK phosphorylation compared to wild-type BRAF, indicating a change in biochemical activity.

Predictive, Oncogenic evidence:

Predictive: The abstract mentions that the FLT-3/Q575Delta mutation can be targeted using available FLT-3 tyrosine kinase inhibitors (TKIs), indicating a correlation with treatment response. This suggests that the variant is predictive of sensitivity to specific therapies.

Oncogenic: The abstract describes the FLT-3/Q575Delta mutation as activating and driving downstream signaling comparable to the well-known FLT-3/ITD mutation, which is associated with tumor development in acute myeloid leukemia (AML). This indicates that the variant contributes to tumor progression, classifying it as oncogenic.

Predictive, Oncogenic evidence:

Predictive: The study discusses the development of KRAS G12C inhibitors, such as sotorasib and adagrasib, and their promising results in treating metastatic NSCLC, indicating a correlation between the G12C variant and response to these therapies.

Oncogenic: The research focuses on KRAS G12C as a somatic variant that contributes to tumor development, particularly in the context of resistance mechanisms against targeted therapies, which is a hallmark of oncogenic behavior.

Diagnostic evidence:

Diagnostic: The study mentions that patients had "RAS and BRAFV600E wild-type tumours," indicating that the presence or absence of the BRAFV600E variant is used to classify the tumors in relation to their HER2 expression status. This suggests that BRAFV600E is relevant for defining the subtype of colorectal cancer in the context of this study.

Predictive, Diagnostic evidence:

Predictive: The study discusses the identification of biomarkers associated with responsiveness to targeted therapies, indicating that certain variants correlate with treatment response in ovarian cancer. This suggests a predictive relationship between the identified biomarkers and the effectiveness of the therapies tested.

Diagnostic: The mention of biomarkers associated with different subsets of patient-derived ovarian cancer xenografts implies that these variants can be used to classify or define specific disease characteristics or treatment eligibility. This aligns with the diagnostic evidence type as it relates to the identification of disease subtypes based on genetic markers.

Predictive, Oncogenic evidence:

Predictive: The study indicates that the FGFR2 EID, including the N173del variant, is associated with sensitivity to FGFR inhibitors, as evidenced by the partial responses observed in patients treated with Debio 1347. This suggests that the presence of this variant can predict therapeutic response to specific treatments targeting FGFR.

Oncogenic: The expression of the FGFR2 EID, which includes the N173del variant, resulted in oncogenic transformation in NIH3T3 cells, indicating that this variant contributes to tumor development and progression. This transformation demonstrates the variant's role in driving cancer biology.

Predictive, Diagnostic evidence:

Predictive: The study discusses the response rates to tazemetostat treatment in patients with EZH2 mutations, indicating that the presence of the EZH2 mutation correlates with a higher objective response rate (69% in the EZH2mut cohort compared to 35% in the EZH2WT cohort). This suggests that the EZH2 mutation is predictive of treatment response to the EZH2 inhibitor.

Diagnostic: The abstract mentions that patients were categorized by their EZH2 mutation status (mutant or wild-type), which indicates that the EZH2 mutation status is used to classify patients with follicular lymphoma. This classification is essential for determining eligibility for the study and treatment with tazemetostat.

Diagnostic, Prognostic evidence:

Diagnostic: The study aims to define the landscape of high-grade gliomas (HGGs) in adolescents and young adults (AYAs) and emphasizes the importance of molecular subgrouping for classification, indicating that specific variants like histone H3 mutations are associated with distinct clinicopathological profiles.

Prognostic: The results highlight that molecular subgrouping has major prognostic importance, suggesting that certain variants correlate with disease outcomes independent of therapy, as the WHO grade was found to have no prognostic value.

Diagnostic, Oncogenic evidence:

Diagnostic: The abstract states that "H3F3A mutations to be specific to GBM and highly prevalent in children and young adults," indicating that the K27M variant is used to classify and define a specific subtype of glioblastoma multiforme (GBM).

Oncogenic: The abstract mentions that the K27M mutation in H3F3A "led to amino acid substitutions at two critical positions within the histone tail," suggesting that this somatic variant contributes to tumor development or progression in glioblastoma.

Predictive, Diagnostic, Prognostic evidence:

Predictive: The study discusses the correlation between PD-L1 expression levels and overall survival (OS) rates in patients treated with avelumab versus docetaxel, indicating that higher PD-L1 expression is associated with improved treatment response. This aligns with the predictive evidence type as it relates to therapy response based on the variant's status.

Diagnostic: The abstract mentions that the primary endpoint was OS in patients with PD-L1+ tumors, which indicates that the presence of PD-L1 expression is used to classify and define a specific patient population for treatment. This supports the diagnostic evidence type as it relates to the identification of a disease subtype based on the variant.

Prognostic: The results highlight the 2-year OS rates for patients with PD-L1+ tumors, demonstrating that the variant correlates with disease outcome independent of therapy. This supports the prognostic evidence type as it discusses survival rates associated with the variant.

Diagnostic, Predisposing evidence:

Diagnostic: The study discusses the substitution of glutamine for arginine in the context of hereditary breast cancer, indicating that this alteration may be involved in the development of the disease. The presence of this variant in patients with bilateral breast cancer suggests its potential role as a biomarker for disease classification.

Predisposing: The variant is described as being present in the germline of patients with hereditary breast cancer, indicating that it confers an inherited risk for developing the disease. The identification of this alteration in patients with a familial history of breast cancer supports its classification as a predisposing variant.

Diagnostic evidence:

Diagnostic: The study discusses the association of initial CD4+ T cell counts of < 200/mm3 with the presence of underlying diseases or tuberculosis, indicating that this variant can be used to classify or define a patient's condition. This aligns with the definition of a diagnostic evidence type, as it relates to identifying disease subtypes based on specific lymphocyte counts.

Predictive, Oncogenic evidence:

Oncogenic: The study discusses how oncogenic fusions involving the NRG1 gene contribute to tumor development and progression, particularly through the activation of HER3 and downstream signaling pathways. The evidence is supported by the observation that seribantumab treatment inhibited growth in cancer cells harboring NRG1 fusions, indicating the role of these fusions in tumorigenesis.

Predictive: The abstract highlights that seribantumab, an anti-HER3 antibody, effectively inhibited the growth of cancer cells with NRG1 fusions, suggesting a correlation between the presence of these variants and sensitivity to this specific therapy. This indicates that NRG1 fusions can predict response to seribantumab treatment in affected cancers.

nan evidence:

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Diagnostic, Oncogenic evidence:

Diagnostic: The study discusses the role of gene fusions in cancer diagnosis and mentions that the CHOP Fusion panel provides genomic information useful for clinical management, indicating its use in defining or classifying disease.

Oncogenic: The abstract states that many fusions encode oncogenic drivers, suggesting that these variants contribute to tumor development or progression.

Oncogenic evidence:

Oncogenic: The study discusses how the MEF2D rearrangements, which include the D30C variant, lead to increased transcriptional activity and cellular transformation in vitro, indicating that this variant contributes to tumor development or progression.

nan evidence:

Missing abstract

nan evidence:

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Diagnostic, Oncogenic evidence:

Diagnostic: The abstract discusses the detection of pathogenic mosaic mutations in genes linked to vascular malformations, indicating that these mutations can be used to confirm the diagnosis of the condition. The mention of "clinicopathological classification" and the importance of molecular analysis suggests that the variant is associated with defining or confirming a disease.

Oncogenic: The abstract notes that the identified mutations, including those in PIK3CA and other genes, are pathogenic and contribute to vascular malformations, which implies a role in tumor development or progression. The context of somatic mosaic mutations further supports the classification of the variant as oncogenic.

Oncogenic evidence:

Oncogenic: The study identifies activating KRAS mutations, specifically KRASG12V, in tissue samples from patients with arteriovenous malformations, suggesting that this somatic variant contributes to tumor development through the activation of the MAPK-ERK signaling pathway in brain endothelial cells.

Oncogenic evidence:

Oncogenic: The variant c.159_173del is described as a small intragenic deletion identified in patients with arteriovenous malformations (AVMs), contributing to the allelic spectrum of variants in the RAS/MAPK pathway, which is known to be pathogenic and involved in tumor development. The context of its identification in affected tissue suggests a role in tumor progression related to AVMs.

Diagnostic, Oncogenic evidence:

Oncogenic: The study discusses that KRAS mutations, including p.G12D and p.G12V, are present in the majority of AVM specimens, indicating that these somatic mutations contribute to tumor development or progression in this context.

Diagnostic: The mention of KRAS mutations being linked to brain AVMs suggests that these variants can be used to classify or confirm the presence of this specific disease, thereby serving a diagnostic purpose.

Diagnostic, Oncogenic evidence:

Oncogenic: The study discusses that KRAS mutations, including p.G12D and p.G12V, are present in the AVM specimens and are described as "likely somatic disease-causing mutations," indicating their role in tumor development or progression.

Diagnostic: The mention of KRAS mutations being linked to brain AVMs suggests that these variants can be used to classify or confirm the presence of the disease, supporting their role as diagnostic markers.

Diagnostic, Oncogenic evidence:

Oncogenic: The study discusses that KRAS mutations, including p.G12D and p.G12V, are present in the AVM specimens and are described as "likely somatic disease-causing mutations," indicating their role in tumor development or progression.

Diagnostic: The mention of KRAS mutations being linked to brain AVMs suggests that these variants can be used to classify or confirm the presence of the disease, supporting their role as diagnostic markers.

nan evidence:

Missing abstract

Oncogenic evidence:

Oncogenic: The study identifies somatic mutations in PIK3CA that contribute to the development of CLOVES syndrome, indicating that these mutations play a role in tumor development or progression, as they are associated with increased phosphoinositide-3-kinase activity, which is a known oncogenic pathway.

Diagnostic, Oncogenic evidence:

Oncogenic: The study discusses that activating mutations of PIK3CA, including p.His1047Arg, function as oncogenes and are widely seen in human cancers, indicating that this variant contributes to tumor development or progression.

Diagnostic: The abstract mentions that the clinical and molecular spectrum of PIK3CA-related developmental disorders is correlated with types of mutations, suggesting that the presence of specific mutations like p.His1047Arg can be used to classify or define these disorders.

Diagnostic, Oncogenic evidence:

Diagnostic: The abstract discusses various diagnostic descriptors associated with PIK3CA mutations, indicating that these mutations are used to classify and define specific segmental overgrowth disorders. This aligns with the definition of the Diagnostic evidence type, as it highlights the association of the variant with distinct clinical phenotypes.

Oncogenic: The results section mentions somatic activating mutations in the growth-promoting serine/threonine kinase AKT1 and other signaling proteins in the RTK/PI3K/AKT/mTOR pathway, which contribute to tumor development in segmental overgrowth syndromes. This supports the Oncogenic evidence type, as it indicates that these mutations play a role in tumor progression.

Diagnostic evidence:

Diagnostic: The study discusses the detection of PIK3CA somatic alterations in the context of the PIK3CA-related overgrowth spectrum (PROS), indicating that these variants are used to classify and confirm the presence of this specific disease. The mention of a diagnostic yield of 71% further supports the role of these variants in defining the condition.

Diagnostic, Oncogenic, Functional evidence:

Diagnostic: The study identifies the cancer-associated p.His1047Leu mutation in PIK3CA in affected cells of a patient with a distinct overgrowth syndrome, suggesting that this variant is used to classify or define the disease.

Oncogenic: The presence of the p.His1047Leu and p.His1047Arg mutations in patients with overlapping syndromes indicates that these somatic variants contribute to tumor development or progression, as they are associated with a syndrome characterized by segmental overgrowth.

Functional: The study demonstrates that affected dermal fibroblasts with the identified mutations show enhanced basal and EGF-stimulated PIP3 generation, indicating that these variants alter molecular function and activate downstream signaling pathways.