Summary: Claude Usage Limits & Cost Analysis

Subscription vs. API Efficiency * Massive Cost Savings: Claude subscriptions can be up to 36x cheaper than using the API for equivalent token throughput. * The "Max 5x" Sweet Spot: The $100/mo Max 5x plan is identified as the most optimized tier, offering roughly 8.3x more weekly usage than the Pro plan (exceeding its "5x" marketing). * The "Max 20x" Diminishing Returns: While the $200/mo tier provides 4x higher short-term (5-hour) burst limits than the Max 5x, its weekly ceiling is only ~2x higher, making it less efficient for consistent long-term work.

Dual-Layer Usage Framework * 5-Hour Rolling Window: Controls "burst" activity. The counter starts at your first prompt; once reached, you must wait for the window to reset. * 7-Day Weekly Ceiling: A hard cap on total "active compute hours" (time spent processing tokens/reasoning). This acts as a global safety valve for the system. * Unified Quota: All usage across the browser (claude.ai), Claude Desktop, and Claude Code (terminal) counts toward the same unified limit.

Token Consumption Dynamics * Exponential Context Cost: Claude re-reads the entire chat history for every new message. A 50-message thread uses significantly more tokens (and quota) than five separate 10-message chats. * Input-Heavy Bias: Large file attachments, long project instructions, and extensive "Extended Thinking" sessions consume the quota much faster than short, text-only queries.

Optimization Strategies * The /compact Command: Users are encouraged to use /compact (in Claude Code) or manually summarize/restart chats every 15–20 messages to reset the "token tax" of long histories. * Lean Context: Keeping CLAUDE.md and project documentation concise prevents "context bloat" from draining limits prematurely. * Strategic Timing: Since the 5-hour window starts with the first prompt, power users should time their first interaction to align with their most intensive coding blocks.

Recommendation: Which Claude Tier is Right for You?

1. The "Value King": Max 5x ($100/mo) * Why it’s recommended: Data analysis shows this tier is "over-provisioned." While marketed as 5x, it often provides ~6x higher session limits and ~8.3x higher weekly limits than the Pro plan. * The Sweet Spot: It offers the best balance between a massive increase in capacity and price. Most daily professional users and developers find it nearly impossible to hit these limits even with "all-day" use. * Best For: Professional developers, heavy researchers, and those who want consistent access to the Claude 3.5 Opus model without hitting daily caps.

2. The "Sprint Specialist": Max 20x ($200/mo) * The Caveat: Despite the name, the weekly ceiling is only ~2x higher than the Max 5x plan, not 4x higher. You are essentially paying for a much higher "burst" capacity. * Why choose it: It allows for extremely high-intensity sessions (up to 900+ messages in 5 hours). This is useful if you do massive "sprints" where you need Claude to process huge amounts of data or code in a very short window. * Best For: Solopreneurs building products in rapid bursts, or users who never want to think about rate limits during a 4–6 hour deep-work session.

3. The "Standard Choice": Pro ($20/mo) * Why it’s recommended: It is 5x cheaper than the next tier and sufficient for 90% of users who use Claude for general writing, light coding, or occasional complex tasks. * Best For: Students, casual coders, and users with small projects (under 1,000 lines of code).

Summary Table * Quick Comparison Summary * Pro: $20/mo | Baseline Capacity | Best for personal/standard use. * Max 5x: $100/mo | ~8.3x Weekly Capacity | Best overall value for power users. * Max 20x: $200/mo | ~16x Weekly Capacity | Best for high-intensity "burst" work.

LLM safety constrains narrow responses to increase predictability

• CLAUDE.md is a special onboarding file to familiarize Claude (an AI code assistant) with your codebase.
• It should clearly outline the WHY (purpose of the project), WHAT (tech stack, project structure, key components), and HOW (development process, running tests, build commands) for Claude.
• The file helps Claude understand your monorepo or multi-application project and know where to look for things without flooding it with unnecessary details.
• Keep CLAUDE.md concise and focused; ideally, it should be under 300 lines, with many recommending less than 60 lines for clarity and relevance.
• Use progressive disclosure: point Claude to where to find further information rather than including all details upfront, avoiding overwhelming the model’s context window.
• Complement CLAUDE.md with tools like linters, code formatters, hooks, and slash commands to separate concerns like implementation and formatting.
• CLAUDE.md is a powerful leverage point for getting better coding assistance but must be carefully crafted—not auto-generated.
• The file should include core commands, environment setup, guidelines, and unexpected behaviors relevant to the repository.
• Encouraging Claude to selectively read or confirm files before use can help maintain focus during sessions.

Hacker News Discussion

• Users emphasized the benefit of explicit instruction patterns like "This is what I'm doing, this is what I expect," which improves monitoring and recovery from errors.
• Some commenters felt these markdown files had marginal gains and that model quality mattered more than the presence of CLAUDE.md.
• A few highlighted the importance of writing documentation primarily for humans rather than solely for LLMs.
• Discussion included anticipation of more stateful LLMs with better memory, which would impact how such onboarding files evolve.
• Recommendations included hierarchical or recursive context structures in CLAUDE.md for large projects, allowing a root file plus targeted sub-files.
• Comments supported having Claude address the user specifically to verify it is following instructions properly.
• Some users noted improvements in model adherence compared to past versions, making CLAUDE.md files more effective now.
• Practical tips were shared for managing large monorepos and integrating CLAUDE.md with version control status.

for - from - LinkedIn post - AI LLM judgment vs human judgment - https://hyp.is/UdbScM05EfC_JWs5FhG-Mg/www.linkedin.com/posts/walterquattrociocchi_ive-never-had-two-editorials-in-top-tier-activity-7399375954743123968-Sn9Y/?rcm=ACoAACc5MHMBii80wYJJmFqll3Aw-nvAjvI52uI

• Article warns about AI hallucinations spreading disinformation in journalism, law, and business, spotlighting Polish journalist Karolina Opolska's book with likely AI-generated fake sources and errors.
• Opolska incident reached 4 million potential contacts (1.6M traditional media, 2.4M social) from Nov 5-19, 2025, impacting 1 in 8 Poles aged 15+; social reaction mostly negative, debating trust in journalists and AI.
• Polish Exdrog firm lost road tender due to AI-fabricated tax interpretations (1.3M reach, Oct 26-Nov 10, 2025).
• Global cases include lawyers citing invented precedents and media promoting nonexistent books; BBC/EBU study shows 45% error rate in tools like ChatGPT, Copilot, Gemini, Perplexity.
• Legal liability unclear (AI maker, provider, or user?); human verification essential.
• AI content red flags: perfect formatting, clickbait, dubious stats like 93% without method, no timelines/methodology, rapid production, overused LLM words (e.g., "kluczowe", "istotne", "kompleksowy", "rewolucyjny").
• IMM analyses from Polish media/social coverage for both cases.

Amazing that MCP is not funtamental.

• Media circulated a claim that Polish language is best for prompting, but this was not a conclusion from the OneRuler study.
• OneRuler is a multilingual benchmark testing how well language models process very long texts in 26 languages.
• Models performed on average best with Polish, but differences compared to English were small and not explained.
• Polish media prematurely concluded Polish is best for prompting, which the study's authors did not claim or investigate.
• The benchmark tested models on finding specific sentences in long texts, akin to CTRL+F, a function AI models inherently lack.
• Another task involved listing the most frequent words in a book; models often failed when asked to acknowledge if an answer was not present.
• Performance dropped likely because the task required full context understanding, not just text searching.
• Different books were used per language (e.g. Polish used "Noce i dnie," English used "Little Women"), impacting the fairness of comparisons.
• The choice of books was based on expired copyrights, which influenced the results.
• There is no conclusive evidence from this benchmark that Polish is superior for prompting due to multiple influencing factors.
• No model achieved 100% accuracy, serving as a caution about language models' limitations; outputs should be verified.
• Researchers advise caution especially when using language models for sensitive or private documents.
• The OneRuler study was reviewed and presented at the CoLM 2025 conference.

nan evidence:

Missing abstract

Predictive, Diagnostic, Oncogenic evidence:

Predictive: The abstract mentions that NF1 mutant melanomas can be effectively treated with EGFR inhibitors, indicating a correlation between the variant and response to therapy.

Diagnostic: The results section describes the identification of mutational profiles in melanoma samples, specifically noting that C>T transitions are characteristic of cutaneous melanoma, which supports the use of this variant in defining the disease subtype.

Oncogenic: The results highlight that the C>T transitions are part of the mutational spectra associated with cutaneous melanoma, suggesting that these somatic variants contribute to tumor development or progression.

Diagnostic, Oncogenic evidence:

Diagnostic: The study mentions that six (4%) of the GBM tumors were IDH1 p.R132H-mutated, indicating that this variant is used to classify or confirm a specific subtype of the disease, which aligns with the definition of a diagnostic evidence type.

Oncogenic: The presence of the IDH1 p.R132H mutation in the tumors suggests that this somatic variant contributes to tumor development or progression, which is characteristic of oncogenic evidence.

nan evidence:

Based on the provided abstract and results section, there is no specific mention of any variants or their implications. Therefore, I cannot classify any evidence types as there are no relevant statements to support any of the CIViC evidence types.

Diagnostic, Functional evidence:

Diagnostic: The abstract discusses the improvement in the accuracy of diagnosis for diffuse gliomas, indicating that the study evaluates genetic/clinical correlations, which may include the variant C228T as part of the diagnostic criteria for glioma classification.

Functional: The results section mentions the mutational analysis of the TERT promoter, specifically referring to the C228T variant, which implies that this variant is being analyzed for its molecular characteristics, such as its role in the context of tumor genetics.

nan evidence:

Missing abstract

Predictive, Functional evidence:

Functional: The study discusses how the mispairing of guanine with thymine during DNA replication, specifically the O6-meG/T mismatch, alters the cellular response to temozolomide treatment by initiating futile cycles of the mismatch repair machinery, leading to DNA damage and cell death. This indicates a change in molecular function due to the variant's presence.

Predictive: The abstract mentions that promoter methylation-mediated silencing of MGMT is associated with increased sensitivity towards temozolomide, suggesting that the guanine-thymine mispairing impacts the response to this specific therapy. This correlation indicates a predictive relationship between the variant and treatment outcome.

nan evidence:

There is no information provided in the abstract or results section regarding the variant(s) mentioned in the paper. Therefore, I cannot classify any evidence types based on the given text.

Diagnostic, Oncogenic evidence:

Diagnostic: The study identifies a de novo pathogenic variant in ELOC (c.236A>G, p.Tyr79Cys) in a proband with VHL disease, suggesting that genetic testing for ELOC variants should be performed in individuals with suspected VHL disease who do not have detectable VHL variants. This indicates the variant's role in classifying or confirming the disease.

Oncogenic: The p.Tyr79Cys substitution is described as a mutational hotspot in sporadic VHL-competent RCC and has been shown to mimic the effects of pVHL deficiency on hypoxic signaling, indicating its contribution to tumor development or progression. This supports the classification of the variant as oncogenic due to its association with cancer-related mechanisms.

Predictive, Oncogenic evidence:

Predictive: The study indicates that AR gene rearrangements in CRPC tumors are associated with resistance to endocrine therapies, specifically mentioning that cell lines with these rearrangements were resistant to the AR antagonist enzalutamide. This suggests a correlation between the variant and treatment response, classifying it as predictive evidence.

Oncogenic: The abstract describes AR gene rearrangements as contributing to the development and progression of CRPC, highlighting their role in promoting the expression of tumor-specific AR variants. This supports the classification of the variant as oncogenic due to its involvement in tumor development.

Predictive, Oncogenic evidence:

Predictive: The study indicates that AR gene rearrangements in CRPC tumors are associated with resistance to endocrine therapies, specifically mentioning that cell lines with these rearrangements were resistant to the AR antagonist enzalutamide. This suggests a correlation between the variant and treatment response, classifying it as predictive evidence.

Oncogenic: The abstract describes AR gene rearrangements as contributing to the development and progression of CRPC, highlighting their role in promoting the expression of tumor-specific AR variants. This supports the classification of the variant as oncogenic due to its involvement in tumor development.

Predictive, Oncogenic evidence:

Predictive: The study indicates that AR gene rearrangements in CRPC tumors are associated with resistance to endocrine therapies, specifically mentioning that cell lines with these rearrangements were resistant to the AR antagonist enzalutamide. This suggests a correlation between the variant and treatment response, classifying it as predictive evidence.

Oncogenic: The abstract states that AR gene rearrangements contribute to the development and progression of CRPC, highlighting their role in tumor-specific AR variant expression. This supports the classification of the variant as oncogenic due to its involvement in tumor development.

Oncogenic evidence:

Oncogenic: The study identifies the 1520C>A mutation (T507K) in the PTPN11 gene as contributing to tumor development, as evidenced by its ability to induce transformed foci in NIH3T3 cells and promote tumor formation in nude mice, indicating its role as an oncoprotein in solid tumors.

Diagnostic evidence:

Diagnostic: The study discusses the potential diagnostic utility of the TRPS1::PLAG1 fusion for determining tumor origin, indicating that this variant can help classify and identify the type of tumor present. The mention of recurrent gene fusions in CMTs and their association with specific histological features further supports its role in disease classification.

Oncogenic evidence:

Oncogenic: The study identifies structural rearrangements involving the PLAG1 gene in chondroid syringomas, specifically the formation of NDRG1-PLAG1 and TRPS1-PLAG1 fusion transcripts, which suggests that these somatic variants contribute to tumor development or progression.

Oncogenic evidence:

Oncogenic: The study identifies structural rearrangements involving the PLAG1 gene in chondroid syringomas, specifically the NDRG1-PLAG1 and TRPS1-PLAG1 fusion transcripts, indicating that these somatic variants contribute to tumor development. The presence of these fusion genes suggests a role in the oncogenic process associated with this type of tumor.

Predictive, Oncogenic evidence:

Predictive: The variant FGFR1 p.V561M is described as imparting resistance to FGFR inhibitors, indicating its role in predicting treatment response and resistance to therapy in the context of pilomyxoid astrocytomas.

Oncogenic: The study identifies the FGFR1 p.V561M variant as a gatekeeper mutation that contributes to tumor development by imparting resistance to inhibitors, suggesting its role in the oncogenic process of pilomyxoid astrocytomas.

Predictive, Oncogenic evidence:

Predictive: The variant FGFR1 p.V561M is described as imparting resistance to FGFR inhibitors, indicating its role in predicting treatment response and resistance in the context of therapy for pilomyxoid astrocytomas.

Oncogenic: The study identifies the FGFR1 p.V561M variant as a gatekeeper mutation that contributes to the tumor's characteristics, suggesting its involvement in tumor development or progression.

nan evidence:

Missing abstract

Predictive, Diagnostic evidence:

Diagnostic: The study discusses the use of FISH analysis for screening ABL1 fusions in pediatric acute lymphoblastic leukemia (ALL), indicating that the presence of the NUP214-ABL1 fusion can be used to classify or confirm the disease. This suggests that the variant is associated with a specific subtype of leukemia, fulfilling the criteria for diagnostic evidence.

Predictive: The abstract mentions that ABL1 fusions are potentially targetable by kinase inhibitors, indicating a correlation between the presence of this variant and the response to specific therapies. This aligns with predictive evidence as it suggests that the variant may influence treatment options.

Functional evidence:

Functional: The variant p.Ser695Leu in EZH2 is mentioned in the context of sequencing results, indicating that it is a mutation found in the patient. This suggests that the variant may alter the molecular function of the EZH2 protein, which is relevant to its role in cancer biology.

nan evidence:

Missing abstract

Oncogenic evidence:

Oncogenic: The study 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, particularly in the context of PARPi-resistant cell lines. This suggests that the variant contributes to the oncogenic processes in these cancer cells.

Predictive, Diagnostic evidence:

Predictive: The study discusses the addition of pembrolizumab to chemotherapy and its impact on disease-free survival (DFS) in patients with dMMR endometrial cancer, indicating a correlation between the dMMR phenotype and treatment response. The results show a significant hazard ratio for DFS in the dMMR population, suggesting that the variant's presence may predict a better response to the therapy.

Diagnostic: The abstract mentions the classification of patients based on their dMMR status, which is used to define a specific subtype of endometrial cancer. This indicates that the dMMR variant is associated with a particular disease phenotype, supporting its role as a diagnostic marker.

Predictive, Prognostic evidence:

Predictive: The study reports that patients with dMMR/MSI-H endometrial cancer treated with dostarlimab plus carboplatin-paclitaxel had a statistically significant reduction in the risk of death, indicating that the variant correlates with response to this specific therapy. The mention of hazard ratios and the context of treatment response supports this classification.

Prognostic: The results indicate a statistically significant overall survival benefit in patients treated with dostarlimab, with a specific hazard ratio reported for the dMMR/MSI-H population, suggesting that the variant correlates with disease outcome independent of therapy. This aligns with the definition of prognostic evidence.

Predictive, Prognostic evidence:

Predictive: The study discusses the significant increase in progression-free survival among patients with dMMR-MSI-H tumors treated with dostarlimab, indicating that the variant correlates with response to this specific therapy. The results show a marked difference in progression-free survival rates between the dostarlimab and placebo groups, highlighting the predictive nature of the variant in relation to treatment efficacy.

Prognostic: The results also provide data on overall survival rates at 24 months, suggesting that the presence of the dMMR-MSI-H variant correlates with better survival outcomes independent of therapy. The hazard ratios reported for both progression-free survival and overall survival indicate that this variant has prognostic implications for patients with endometrial cancer.

Predictive, Oncogenic evidence:

Predictive: The study discusses how alterations in specific tumor suppressor genes, including the Kras G12D variant, can identify patients likely to benefit from immune checkpoint inhibitors combined with chemotherapy, indicating a correlation with treatment response.

Oncogenic: The variant Kras G12D is part of a genetically engineered model used to assess its role in promoting tumor growth, demonstrating its contribution to tumor development in the context of lung cancer.

Predictive, Diagnostic evidence:

Predictive: The study investigates the efficacy of Debio 1347, a selective inhibitor targeting FGFR1-3 fusions, in patients with solid tumors harboring these fusions, indicating a focus on treatment response. The mention of "objective response rate (ORR)" and the evaluation of efficacy directly relates to the predictive nature of the variant's impact on therapy response.

Diagnostic: The abstract states that the trial involved patients with tumors "harboring a functional FGFR1-3 fusion," which implies that the presence of these fusions is used to classify or define the patient population for the study, thus supporting a diagnostic classification.

Predictive, Diagnostic evidence:

Diagnostic: The study discusses the t(4;14) translocation as a characteristic found in approximately 15% of patients with multiple myeloma, indicating its role in classifying patients based on their genetic status. This classification is essential for understanding the disease and tailoring treatment approaches.

Predictive: The study evaluates the efficacy of dovitinib, an RTK inhibitor, in patients with relapsed or refractory multiple myeloma, specifically assessing the treatment response based on the presence of the t(4;14) translocation. The mention of treatment response rates in relation to the t(4;14) status suggests a predictive relationship between the variant and therapy outcomes.

Predictive, Oncogenic evidence:

Predictive: The study discusses the efficacy of fexagratinib, an FGFR inhibitor, in patients with recurrent FGFR-TACC + high-grade gliomas, indicating a correlation between the FGFR-TACC fusion and response to this specific therapy. The mention of a 32-gene signature associated with the benefit of FGFR inhibition further supports the predictive nature of the variant in relation to treatment response.

Oncogenic: The abstract states that FGFR-TACC fusions are oncogenic and present in high-grade gliomas, indicating that these somatic variants contribute to tumor development or progression. This classification is supported by the context of the study focusing on the safety and efficacy of a treatment targeting these specific fusions.

Oncogenic evidence:

Oncogenic: The variant K27M is associated with the histone H3 K27M mutant protein, which is known to contribute to tumor development or progression in certain cancers, particularly gliomas. The mention of this specific mutant protein in the results section indicates its role in oncogenesis.

Diagnostic evidence:

Diagnostic: The abstract discusses HGAP as an important consideration in the differential diagnosis of isocitrate dehydrogenase-wild-type gliomas, indicating that the variant is used to classify or define a disease subtype. Additionally, it mentions the association with neurofibromatosis 1 syndrome, further supporting its role in diagnosis.

Diagnostic, Predisposing evidence:

Diagnostic: The study discusses the identification of germline mutations in patients with pheochromocytomas and paragangliomas (PPGLs), indicating that these variants can lead to an early diagnosis of multiple or more aggressive tumors, which aligns with the use of variants to define or confirm a disease.

Predisposing: The mention of germline mutations in patients with PPGLs suggests an inherited risk for developing these tumors, particularly in younger patients, which supports the classification of these variants as predisposing.

Predictive, Prognostic, Oncogenic evidence:

Predictive: The study discusses the variant G2032R in the context of acquired resistance mutations, indicating that taletrectinib shows robust activity against this variant, which correlates with treatment response. This suggests that the presence of G2032R may influence the effectiveness of taletrectinib therapy in patients with NSCLC.

Prognostic: The results mention prolonged progression-free survival associated with taletrectinib treatment, which implies that the presence of the G2032R variant may correlate with disease outcome independent of therapy. This indicates that the variant could have implications for patient prognosis in the context of treatment with taletrectinib.

Oncogenic: The mention of G2032R as an acquired resistance mutation suggests that it contributes to tumor progression or development, particularly in the context of resistance to therapy. This aligns with the definition of an oncogenic variant, as it is involved in the cancer's response to treatment.

Predictive, Oncogenic evidence:

Predictive: The study discusses the drug sensitivity and resistance of the exon 20 insertion variants, specifically mentioning that they have lower sensitivity to 1st-3rd generation EGFR TKIs and that newer inhibitors like BAY-568, TAS6417, and TAK-788 show selective inhibition, indicating a correlation with treatment response.

Oncogenic: The abstract highlights that somatic mutations in EGFR, including the exon 20 insertions, are frequent drivers of non-small cell lung cancer (NSCLC), which supports the notion that these variants contribute to tumor development and progression.

Predictive evidence:

Predictive: The study demonstrates that treatment with osimertinib significantly improves progression-free survival in patients with unresectable EGFR-mutated NSCLC, indicating a correlation between the EGFR mutation and response to this specific therapy. The results show a median progression-free survival of 39.1 months with osimertinib compared to 5.6 months with placebo, highlighting the predictive nature of the EGFR variant in treatment outcomes.

Predictive, Diagnostic evidence:

Diagnostic: The variant M34 is associated with the pathology diagnosis of LUSC (lung squamous cell carcinoma) in the context of the study, indicating its relevance in defining or classifying this disease subtype.

Predictive: The results indicate that patients with the M34 variant received first-line treatment with chemo+pembrolizumab, and the best response was complete response (CR), suggesting a correlation between this variant and treatment response.

Prognostic, Functional evidence:

Prognostic: The abstract mentions that "Osteosarcoma (OS) patients with metastasis or recurrent tumors still suffer from poor prognosis," indicating a correlation between the variant and disease outcome independent of therapy.

Functional: The study discusses how treatment with the DNA demethylating agent 5-aza-2'-deoxycytidine (5-aza-dC) "markedly suppressed their growth" and "multiple tumor-suppressor and osteo/chondrogenesis-related genes were re-activated," suggesting that the variant alters molecular function related to gene expression and cellular behavior.

Predictive evidence:

Predictive: The abstract indicates that selective TRK inhibition by larotrectinib is a therapeutic option specifically for IFS carrying the ETV6-NTRK3 gene fusion, suggesting a correlation between this variant and response to therapy. This aligns with the definition of predictive evidence, as it discusses the effectiveness of a treatment based on the presence of a specific variant.

Diagnostic, Prognostic evidence:

Diagnostic: The study discusses kataegis in the context of breast cancer subgroups defined by ER, PR, and HER2/ERBB2 status, indicating its role in classifying and associating with specific tumor characteristics and aggressive phenotypes.

Prognostic: The abstract mentions that kataegis status was associated with aggressive characteristics in certain breast cancer subgroups, suggesting a correlation with disease outcome, particularly in ERpHER2n tumors.

Predictive, Diagnostic evidence:

Diagnostic: The study identifies the Ph-like gene expression profile and its association with specific genomic alterations in childhood B-lineage ALL, indicating that these genetic lesions can be used to classify and define this high-risk subtype of leukemia.

Predictive: The findings suggest that the identified targetable genetic lesions, such as CRLF2 rearrangements and ABL-class fusions, may correlate with treatment approaches in precision medicine for Ph-like ALL, indicating their potential role in predicting response to targeted therapies.

Predictive, Diagnostic evidence:

Diagnostic: The study identifies the Ph-like gene expression profile and its association with high-risk childhood B-lineage ALL, indicating that specific genetic alterations can be used to classify and define this subtype of leukemia.

Predictive: The findings suggest that the identified targetable genetic lesions, such as CRLF2 rearrangements and ABL-class fusions, may correlate with treatment approaches in precision medicine for Ph-like ALL, indicating potential sensitivity to specific therapies.

Predictive, Diagnostic evidence:

Diagnostic: The study identifies the Ph-like gene expression profile and its association with specific genetic alterations in childhood B-lineage ALL, indicating its role in classifying this high-risk subtype of leukemia.

Predictive: The findings support a precision-medicine approach for Ph-like ALL, suggesting that the identified genetic lesions may correlate with response to targeted therapies, which is a key aspect of treatment for this subtype.

Predictive, Diagnostic evidence:

Diagnostic: The study identifies the Ph-like gene expression profile and its association with specific genetic alterations in childhood B-lineage ALL, indicating its role in classifying this high-risk subtype of leukemia. The mention of the frequency of CRLF2 rearrangements and other genetic lesions further supports the use of these variants in defining the disease.

Predictive: The findings suggest that the identified genetic alterations, including CRLF2 rearrangements and other targetable lesions, may correlate with treatment approaches in precision medicine for Ph-like ALL, indicating their potential impact on therapy response. The emphasis on targetable genetic lesions implies a relationship with treatment strategies.

Predictive, Diagnostic evidence:

Diagnostic: The study identifies the Ph-like gene expression profile and its association with high-risk childhood B-lineage ALL, indicating that specific genomic alterations can be used to classify and define this subtype of leukemia.

Predictive: The findings suggest that the identified targetable genetic lesions, such as CRLF2 rearrangements and ABL-class fusions, may correlate with treatment approaches in precision medicine for Ph-like ALL, indicating potential sensitivity to specific therapies.

Predictive, Diagnostic evidence:

Diagnostic: The study identifies the Ph-like gene expression profile and its association with specific genetic alterations in childhood B-lineage ALL, indicating that these variants can be used to classify and define this high-risk subtype of leukemia.

Predictive: The findings suggest that the identified genetic lesions, including CRLF2 rearrangements and other targetable alterations, may correlate with treatment response in the context of precision medicine for Ph-like ALL, highlighting their potential role in guiding therapy.

Predictive, Diagnostic evidence:

Diagnostic: The study identifies the Ph-like gene expression profile and its association with specific genetic alterations in childhood B-lineage ALL, indicating its role in classifying this high-risk subtype of leukemia. The mention of the frequency of CRLF2 rearrangements and other genomic alterations further supports the use of these variants in defining the disease.

Predictive: The findings suggest that the identified genetic lesions, including CRLF2 rearrangements and other targetable alterations, may correlate with treatment approaches in precision medicine for Ph-like ALL, indicating their potential impact on therapy response. The emphasis on targetable genetic lesions implies a relationship with treatment strategies.

Diagnostic, Prognostic evidence:

Prognostic: The study reports that higher numbers of somatic mutations and copy number alterations (CNAs) significantly correlated with worse survival, indicating that these genetic alterations are associated with disease outcomes independent of therapy. Additionally, it identifies specific mutations and amplifications, such as PD-L1, as independent poor prognostic factors in aggressive ATL, further supporting the prognostic nature of these findings.

Diagnostic: The abstract mentions that aggressive and indolent ATL subtypes are associated with different genetic alterations, which helps classify the disease into molecularly distinct subsets. This classification based on genetic profiles indicates the use of these variants in defining and understanding the disease subtypes.

Predictive, Oncogenic evidence:

Predictive: The study discusses the association of the L858R mutation with treatment outcomes, indicating that patients with this mutation have a similar overall survival (OS) compared to those with uncommon, actionable variants when treated with first-line EGFR inhibitors. This suggests that the presence of the L858R variant correlates with response to therapy, which is a key aspect of predictive evidence.

Oncogenic: The abstract mentions that activating mutations in EGFR, including L858R, are a common mechanism of malignant transformation in non-small cell lung cancer (NSCLC). This indicates that the L858R variant contributes to tumor development, supporting its classification as oncogenic.

Predictive, Prognostic evidence:

Predictive: The abstract mentions that testing for driver mutations identifies patients who benefit from TKI-therapy, indicating that the presence of such mutations, including T790M, correlates with response to specific therapies. Additionally, the results highlight that the presence of a driver mutation predicts response to specific TKIs, further supporting the predictive nature of the T790M variant in the context of treatment.

Prognostic: The results section states that EGFR-positive NSCLC is associated with improved prognosis, suggesting that the presence of the T790M variant may correlate with disease outcomes independent of therapy. This indicates that T790M could have prognostic implications in the context of NSCLC.

Diagnostic, Oncogenic evidence:

Diagnostic: The variant p.V617F is mentioned as a major diagnostic criterion for the diagnosis of Polycythemia Vera (PV), indicating its role in defining and confirming the disease. The presence of this mutation is used to classify the disease, which aligns with the definition of a diagnostic evidence type.

Oncogenic: The mention of the JAK2 p.V617F mutation in the context of diagnostic criteria for PV suggests that it contributes to tumor development or progression, as it is a well-known somatic mutation associated with myeloproliferative neoplasms. This aligns with the oncogenic evidence type, as it indicates the variant's role in the pathogenesis of the disease.

nan evidence:

Parsing error: argument of type 'NoneType' is not iterable

Predictive, Diagnostic evidence:

Diagnostic: The study evaluates the immunophenotypes and karyotypes of patients with childhood acute lymphoblastic leukemia (ALL) associated with the t(1;19) and der(19)t(1;19) translocations, suggesting that these variants can be used to classify distinct subtypes of ALL.

Predictive: The results indicate that patients with the t(1;19) and der(19)t(1;19) translocations did not respond to therapy as well as those with early pre-B ALL, highlighting the predictive nature of these variants in terms of treatment response.

Predictive, Diagnostic evidence:

Predictive: The identification of the COL1A1-PDGFB gene fusion allows greater choice of targeted therapy in these patients, indicating that the variant correlates with response to specific therapies.

Diagnostic: The COL1A1-PDGFB gene fusion is associated with a specific subtype of uterine sarcoma, which supports its use in defining and classifying this disease entity.

Predictive, Diagnostic evidence:

Diagnostic: The study identifies the SH3PXD2A::HTRA1 fusion in schwannomas and discusses its prevalence and association with specific clinicopathologic characteristics, indicating its role in defining and classifying these tumors. The mention of "fusion-positive schwannomas" and their distinct features supports the classification of this variant as a diagnostic marker.

Predictive: The study establishes a correlation between the presence of the SH3PXD2A::HTRA1 fusion and specific histological features, such as the 'serpentine' palisading pattern, which can predict fusion status with high sensitivity and specificity. This suggests that the variant may be used to predict certain characteristics of the tumors, aligning with predictive evidence.

nan evidence:

Based on the provided information, there are no mentions of the variant in either the abstract or the results section. Therefore, I cannot classify any evidence type as there is no supporting text to justify a classification.

nan evidence:

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Diagnostic, Oncogenic evidence:

Oncogenic: The abstract discusses the identification of EGFR internal tandem duplications (ITD) in tumors, specifically noting their presence in congenital mesoblastic nephromas and other pediatric sarcomas. This suggests that the EGFR ITD contributes to tumor development or progression in these specific cancer types.

Diagnostic: The study highlights the association of EGFR ITD with specific tumor types, particularly in pediatric sarcomas, indicating its role in defining or classifying these tumors. The identification of this variant in a subset of tumors supports its use as a biomarker for diagnosis.

Prognostic evidence:

Prognostic: The study indicates that adult patients with t(1;19)(q23;p13) positive ALL had a favorable prognosis, as evidenced by the reported 5-year cumulative incidence of relapse and overall survival rates. This suggests that the variant correlates with disease outcome independent of therapy.

Diagnostic, Prognostic evidence:

Prognostic: The study indicates that the t(1;19) variant is an independent risk factor for isolated CNS relapse, suggesting that it correlates with disease outcome independent of therapy. This is supported by the mention of event-free survival and the cumulative incidence of relapse in patients with this variant.

Diagnostic: The t(1;19) is used to classify and define a specific subtype of B-cell precursor acute lymphoblastic leukemia (ALL), as indicated by its association with the TCF3/PBX1 fusion. This classification is crucial for understanding the disease and its treatment implications.

Diagnostic, Oncogenic evidence:

Diagnostic: The study discusses the t(1;19) chromosomal translocation as being observed in 25% of children with pre-B-cell acute lymphoblastic leukemia (ALL) and highlights its association with an adverse treatment outcome, indicating its role in defining and classifying the disease. The detection of E2A/PBX1 fusion transcripts in a majority of cases further supports its use as a biomarker for this subtype of leukemia.

Oncogenic: The findings suggest that the E2A/PBX1 fusion resulting from the t(1;19) translocation is an important pathogenic event in t(1;19) ALL, indicating that this somatic variant contributes to tumor development or progression in this specific leukemia type.

Diagnostic, Oncogenic evidence:

Diagnostic: The study discusses the t(1;19) translocation and its association with acute lymphoblastic leukemia (ALL), indicating that it is a common genetic alteration used to classify the disease. The mention of different mechanisms leading to the formation of the der(19) and the investigation of markers proximal to the breakpoint further supports its role in defining the disease subtype.

Oncogenic: The t(1;19) translocation is described as one of the most common translocations in ALL, suggesting that it contributes to tumor development or progression. The study's focus on the mechanisms of how the der(19) arises indicates its potential role in oncogenesis within the context of leukemia.

nan evidence:

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Predictive, Diagnostic evidence:

Diagnostic: The study discusses the identification of patients with E2A-PBX1 positive translocations, indicating that the presence of this specific variant is used to classify and confirm a subtype of acute lymphoblastic leukemia (ALL). The development of a fluorescence in situ hybridization assay to detect E2A translocations further supports its role as a diagnostic tool in identifying patients who require specific therapeutic interventions.

Predictive: The abstract mentions that more intensive therapy improves the outcome of patients with E2A-PBX1 positive translocations, suggesting that the presence of this variant correlates with response to therapy. This highlights the importance of identifying this subset of patients to administer appropriate treatment, which aligns with predictive evidence.

Oncogenic evidence:

Oncogenic: The study discusses the translocation t(12;16)(q13:p11) in malignant myxoid liposarcoma, indicating that it results in a fusion of the CHOP gene with the FUS gene, which contributes to tumor development. This suggests that the variant plays a role in the oncogenic process by creating a fusion protein that may drive tumorigenesis.

Prognostic evidence:

Prognostic: The study demonstrates the prognostic significance of genetic alterations within subtypes of acute lymphoblastic leukemia (ALL), indicating that these alterations correlate with disease outcomes. This suggests that the presence of specific genetic changes can provide insights into the prognosis of patients with different ALL subtypes.

Prognostic evidence:

Prognostic: The study demonstrates the prognostic significance of genetic alterations within subtypes of acute lymphoblastic leukemia (ALL), indicating that these alterations correlate with disease outcomes. This suggests that the presence of specific genetic changes can provide insights into the prognosis of patients with ALL.

Prognostic evidence:

Prognostic: The study demonstrates the prognostic significance of genetic alterations within subtypes of acute lymphoblastic leukemia (ALL), indicating that these alterations correlate with disease outcomes. This suggests that the presence of specific genetic changes can provide insights into the prognosis of patients with ALL.

nan evidence:

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Predictive, Oncogenic evidence:

Predictive: The study discusses the efficacy of BI-4732 in overcoming osimertinib resistance mediated by the C797S variant, indicating that this variant correlates with resistance to therapy and highlights the potential for BI-4732 as a treatment option.

Oncogenic: The C797S variant is implicated in osimertinib resistance, suggesting that it contributes to tumor progression and development, as evidenced by the preclinical models used in the study.

Predictive, Oncogenic evidence:

Predictive: The study discusses the resistance to CDK4/6 inhibitors in KRAS-mutant non-small cell lung cancer (NSCLC) and how the inhibition of BRD4 can enhance the efficacy of these inhibitors, indicating a correlation with treatment response. The mention of "synergized with palbociclib to induce senescence" suggests that the variant's presence affects the sensitivity to therapy.

Oncogenic: The abstract indicates that BRD4 overexpression contributes to resistance against CDK4/6 inhibitors in KRAS-mutant NSCLC cells, suggesting that this variant plays a role in tumor progression and development. The context of BRD4's involvement in enhancing cell cycle arrest and promoting senescence further supports its oncogenic role.

Predictive evidence:

Predictive: The abstract mentions that PLX8725 demonstrates promising in vivo activity against PDX models of uLMS harboring GOF alterations in the MAP2K4 gene, indicating a correlation between the variant and response to the therapy. This suggests that the variant may influence treatment sensitivity, warranting further clinical trials.

Predictive, Oncogenic evidence:

Predictive: The study evaluates the response to divarasib, a KRAS G12C inhibitor, in patients with tumors harboring the KRAS G12C mutation, indicating that the variant correlates with treatment response. The mention of "biomarkers of response and resistance" further supports the predictive nature of the evidence regarding therapy outcomes.

Oncogenic: The KRAS G12C mutation is described as a target for the covalent inhibitor divarasib, suggesting that this somatic variant contributes to tumor development or progression. The context of the study focuses on advanced or metastatic solid tumors that harbor this mutation, reinforcing its role in oncogenesis.

Predictive evidence:

Predictive: The study indicates that SRSF2- and U2AF1-mutant leukemias are preferentially sensitive to PARP inhibitors, suggesting a correlation between these mutations and response to therapy. The mention of "PARPi sensitivity" and "PARP1 activity could be predictive of PARPi sensitivity" directly supports the predictive nature of the variant's role in treatment response.

Predictive, Oncogenic evidence:

Predictive: The study discusses the efficacy of the PRMT5 methyltransferase inhibitor MRTX1719 in selectively killing cancers that are codeleted for CDKN2A and MTAP, indicating a correlation between the CDKN2A/MTAP codeletion and response to this specific therapy. This suggests that the presence of the variant is predictive of treatment response in clinical trials for solid tumors.

Oncogenic: The abstract mentions that CDKN2A is the most common homozygously deleted gene in all human cancers, indicating that its deletion contributes to tumor development or progression. This supports the classification of CDKN2A as an oncogenic variant due to its role in cancer biology.

Diagnostic, Oncogenic evidence:

Diagnostic: The study identifies NRG1 fusions as occurring in 0.36% of lung adenocarcinoma cases and discusses their prevalence among specific pathologic subtypes, indicating that these fusions can be used to classify or define a subset of lung cancer.

Oncogenic: The presence of NRG1 fusions, along with other fusions detected in the study, suggests that these alterations contribute to tumor development or progression in lung adenocarcinomas, as they are described in the context of profiling oncogenic drivers.

Predictive evidence:

Predictive: The results indicate that the RET gatekeeper mutations V804L/M/E are specifically mentioned in the context of treatment with RET-specific TKIs, selpercatinib and pralsetinib, which are approved for RET-altered cancers. This suggests that these variants correlate with response to these therapies, highlighting their predictive nature regarding treatment efficacy.

Diagnostic, Oncogenic evidence:

Diagnostic: The study identifies the prevalence of the ERBB2DeltaEx16 variant, including c.1899-880_1946+761del, in Chinese pan-cancer patients, suggesting its role in defining or classifying a disease subtype within this population.

Oncogenic: The presence of the c.1899-880_1946+761del variant among the detected ERBB2DeltaEx16 variants indicates its potential contribution to tumor development or progression, as it is part of a broader category of variants associated with the ERBB2 gene in cancer.

Predictive, Diagnostic evidence:

Predictive: The study reports that the patient carrying the HER2 G292R variant benefited from pyrotinib treatment after progression on prior therapies, indicating a correlation between this variant and a positive response to a specific therapy.

Diagnostic: The mention of the HER2 G292R variant in the context of a metastatic cervical adenocarcinoma patient suggests its role in defining or classifying the disease, particularly as it is associated with activating mutations in HER2 commonly found in this cancer type.

Predictive, Diagnostic evidence:

Predictive: The study demonstrates that the p.L755P mutation correlates with a response to osimertinib treatment in a patient with NSCLC, indicating its potential as a predictive biomarker for therapy response.

Diagnostic: The mention of the p.L755P mutation in the context of defining the patient's cancer subtype (HER2 exon 19 mutation) suggests that this variant is used to classify or confirm the disease.

Predictive, Prognostic evidence:

Predictive: The study assesses the efficacy of pyrotinib in patients with HER2-mutant advanced NSCLC, indicating that the presence of HER2 mutations correlates with response to this specific therapy, as evidenced by the reported objective response rate of 30.0%.

Prognostic: The median overall survival of 14.4 months for patients with HER2-mutant NSCLC suggests that this variant may correlate with disease outcome, independent of therapy, providing prognostic information about the survival of these patients.

Predictive, Prognostic evidence:

Predictive: The study discusses the effectiveness of trastuzumab deruxtecan in patients with HER2-low metastatic breast cancer, indicating that the variant correlates with response to this specific therapy, as evidenced by the significant differences in progression-free survival and overall survival between treatment groups.

Prognostic: The results show that patients with HER2-low metastatic breast cancer had different overall survival rates based on the treatment received, suggesting that the HER2-low status is associated with disease outcomes independent of therapy.

Predictive, Prognostic evidence:

Predictive: The study discusses the effectiveness of trastuzumab deruxtecan in patients with HER2-low metastatic breast cancer, indicating that the variant correlates with response to this specific therapy, as evidenced by the significant improvement in progression-free survival and overall survival compared to the physician's choice of chemotherapy.

Prognostic: The results show that patients with HER2-low metastatic breast cancer had different overall survival rates based on the treatment received, suggesting that the HER2-low status is associated with disease outcomes independent of therapy, as indicated by the reported hazard ratios for death.

Functional evidence:

Functional: The study discusses PAK4, a serine/threonine kinase, and its role in altering molecular functions related to cancer progression, such as controlling cell proliferation and survival. This indicates that the variant affects biochemical pathways and cellular behaviors, which aligns with the functional evidence type.

Predictive, Oncogenic evidence:

Oncogenic: The study discusses the common mutations in FGFR3, specifically mentioning the S249 mutation, and indicates that these mutations contribute to tumor development, as they are described as "somatic activating mutations" that are prevalent in human cancer.

Predictive: The abstract mentions that the study evaluated the sensitivity of various FGFR mutations, including S249, to FGFR tyrosine kinase inhibitors (TKIs), indicating a correlation between the variant and response to therapy.

Predictive, Oncogenic evidence:

Predictive: The study discusses the potential of a combination treatment using DNA hypomethylating agents and PARP inhibitors specifically targeting SETD2-deficient cancers, indicating a correlation with treatment response in these cases. The mention of "synergistically increased cytotoxicity" in SETD2-deficient cell lines supports the predictive nature of the variant's role in therapy response.

Oncogenic: The abstract highlights that SETD2 deficiency plays a significant role in aggressive forms of cancer, particularly in clear cell renal cell carcinomas, suggesting that this somatic variant contributes to tumor development and progression. The context of "SETD2 deficiency alters the epigenetic landscape" further supports its oncogenic classification.

Predictive, Oncogenic evidence:

Predictive: The study discusses the KRASG12D mutation in the context of therapy, specifically mentioning the response to the MRTX1133 inhibitor and its effects on pancreatic adenocarcinoma (PDAC). The results indicate that MRTX1133 leads to regression of advanced PDAC and highlights the importance of CD8+ T cells and immune checkpoint blockade in enhancing treatment efficacy, which aligns with predictive evidence regarding therapy response.

Oncogenic: The KRASG12D mutation is described as being present in nearly half of pancreatic adenocarcinomas and is implicated in tumor development and progression, as evidenced by the use of various models of KRASG12D-driven PDAC. The study demonstrates that inhibiting this mutation leads to significant changes in tumor growth and microenvironment, supporting its role as an oncogenic driver.

Predictive, Oncogenic evidence:

Predictive: The study discusses how FGFR2 fusions are associated with moderate response rates to FGFR inhibitors and highlights the emergence of resistance due to secondary mutations, indicating a correlation between the FGFR2 variant and treatment response. The findings suggest that combining FGFR and EGFR inhibitors could enhance therapeutic efficacy, further supporting the predictive nature of the FGFR2 variant in treatment contexts.

Oncogenic: The abstract mentions that FGFR2 fusions are present in cholangiocarcinoma and that these fusions contribute to tumor development and progression, as evidenced by the therapeutic studies conducted on patient-derived models. This indicates that the FGFR2 variant plays a role in oncogenesis within this cancer type.

Predictive, Diagnostic evidence:

Predictive: The study discusses the clinical activity of pralsetinib, a selective RET inhibitor, in patients with RET fusion-positive NSCLC, indicating a correlation between the presence of the RET fusion and the response to this specific therapy. The overall response rates reported for treatment-naive patients and those with prior chemotherapy further support this predictive evidence.

Diagnostic: The presence of RET fusions is highlighted as a defining characteristic in the context of non-small-cell lung cancer (NSCLC), suggesting that these variants are used to classify patients with this disease subtype. The mention of RET fusion-positive NSCLC indicates its role as a biomarker for diagnosis.

Functional evidence:

Functional: The variant D9E is mentioned in the context of pAKT-S473, indicating that it is associated with the phosphorylation state of AKT, which suggests that it alters molecular function related to signaling pathways in breast cancer cells. This aligns with the definition of functional evidence as it focuses on the biochemical activity of the protein.

Predictive, Oncogenic evidence:

Predictive: The study discusses how specific FGFR3 mutations, including N540K, result in distinct changes in drug efficacy when treated with various inhibitors, indicating a correlation between the variant and response to therapy.

Oncogenic: The abstract mentions that certain mutations in FGFRs, including N540K, are implicated as drivers in diverse tumors, suggesting their role in tumor development or progression.

Predictive, Diagnostic evidence:

Diagnostic: The study discusses the presence of the R678Q mutation in various breast cancer subtypes, indicating its association with specific histological types such as invasive lobular carcinoma (ILC) and invasive ductal carcinoma (IDC). This suggests that the variant can be used to classify or define the disease based on tumor type.

Predictive: The abstract mentions that patients carrying the R678Q mutation seem to be good candidates for anti-HER2 therapy, as they show favorable outcomes and a good response to current pharmacological treatments. This indicates a correlation between the variant and the response to therapy, classifying it as predictive evidence.

Oncogenic evidence:

Oncogenic: The introduction of the ERBB2 mutation S310F into human pancreatic epithelial cells causes oncogenic transformation, increasing ERBB2 signaling and promoting tumor growth, indicating that it contributes to tumor development.

Oncogenic evidence:

Oncogenic: The abstract discusses the KRAS protein as a common driver in human cancer, indicating that mutations in KRAS, including those at the Q61 position, contribute to tumor development and progression. The results section further emphasizes the oncogenic nature of KRAS mutations, particularly highlighting their prevalence in various cancers.

nan evidence:

There are no mentions of the variant in the abstract or results section provided. Therefore, no CIViC evidence types can be classified based on the information given.

Predictive, Oncogenic evidence:

Predictive: The study indicates that the ALK Arg1275Gln mutation is the only mutation predicted to be sensitive to ALK inhibition with crizotinib, suggesting a correlation between this variant and response to therapy.

Oncogenic: The presence of the somatic ALK Arg1275Gln mutation is described as the most common ALK hotspot mutation observed in neuroblastoma, indicating its role in tumor development or progression.

Predictive, Diagnostic evidence:

Predictive: The study discusses the response of patients with KRAS G12D-mutant NSCLC to bortezomib, indicating that exceptional responses can be achieved, which correlates with treatment sensitivity. The mention of "KRAS G12D mutation alone, however, is not a robust predictor of response" suggests a nuanced relationship between the variant and therapy response.

Diagnostic: The abstract states that patients with advanced KRAS G12D-mutant NSCLC were eligible for the trial, indicating that the presence of this variant is used to classify and define a specific subtype of lung cancer. This aligns with the use of the variant as a biomarker for patient selection in clinical trials.

Oncogenic, Functional evidence:

Functional: The study discusses the variant E401G in the context of its location in the extracellular domain of the ERBB2 gene, indicating that functional analyses of such variants have been limited, which suggests an exploration of how this variant may alter molecular function.

Oncogenic: The mention of ERBB2 gene alterations, including the E401G variant, as promising target alterations in cancer treatment implies that this variant may contribute to tumor development or progression, aligning with oncogenic behavior.

Predictive, Functional evidence:

Predictive: The study indicates that patients with the S310F mutation responded to trastuzumab with or without the pertuzumab combination, suggesting a correlation between the variant and treatment response. This aligns with the predictive evidence type as it discusses the variant's impact on therapy effectiveness.

Functional: The research demonstrates that the S310F mutant HER2 can form an active heterodimer with EGFR, which is a functional alteration in molecular interactions. This evidence supports the functional type as it focuses on the biochemical behavior of the variant in relation to receptor activation and dimerization.

Predictive, Oncogenic evidence:

Predictive: The study discusses the emergence of the ESR1 Y537S mutation in the context of resistance to CDK4/6 inhibitors, indicating that this variant may correlate with treatment resistance, which is a key aspect of predictive evidence.

Oncogenic: The emergence of the ESR1 Y537S mutation is implicated in the development of resistance mechanisms during treatment, suggesting that this somatic variant contributes to tumor progression in the context of advanced breast cancer.

Functional evidence:

Functional: The study discusses the effects of various treatments on the expression of cyclin E and the levels of phosphorylated histone variant H2AX (gammaH2AX), indicating that the variant E in 72 alters molecular function related to DNA damage response and cell cycle regulation. This is supported by the immunoblotting results showing changes in protein expression levels in response to treatment.

Predictive, Oncogenic evidence:

Predictive: The study indicates that HP breast cancers with the HER2V777L mutation show resistance to the pan-HER tyrosine kinase inhibitor, neratinib, but respond effectively to the combination of neratinib and trastuzumab deruxtecan, demonstrating a correlation between the variant and treatment response.

Oncogenic: The presence of the HER2V777L mutation is associated with accelerated tumor formation and increased invasion and migration in breast cancer models, indicating that this somatic variant contributes to tumor development and progression.

Diagnostic, Functional evidence:

Functional: The study discusses the functional analysis of RAD51C variants, including p.Leu262Val (L262V), indicating that this variant was predicted to cause aberrant splicing based on the Splice AI algorithm. This suggests that the variant alters molecular function, specifically splicing activity.

Diagnostic: The abstract mentions that the analysis provides information for the classification of the cancer relevance of RAD51C variants, implying that variants like p.Leu262Val (L262V) are used to define or classify disease relevance, which aligns with diagnostic evidence.