Good way to say "we defined this as..."

Are they saying this was the baseline they used to compare? As in, they just assumed it was the standard, or this was the standard simply because of circumstances?

Very cool, as this aligns with the research I am interested in. Mirrors it in a way.

It would have been nice to see data supporting these subgroupings.

Also, it's cool that I will be using IRT. Used to determine if the distances from 1-2, 2-3, 3-4, & 4-5 are mathematically the same on a Likert-type scale.

Cool to see this in practice. My research turns self-efficacy into several different subgroups in a similar fashion.

Specifically noting only two potential outcomes for descriptive data. Coded as: Male = 0 & Female = 1 for example

Can you measure, for example, all 1st graders in a district, then the following year, all 2nd graders, 3rd, 4th, etc... and just assume that with a large sample size, the data is apples to apples?

Longitudinal and extant

This feels like a strong hypothesis that was well written.

But also, we know students are already overtested, and even so, these tests are often heavily biased to favor the dominant group.

This feels off. A big difference between research and evaluation is that research asks few, specific, and concise questions while evaluations go for as much bang for your buck. This first research question looks like it is stretched to thin by having two questions attached to it.

The cliche nature vs nurture argument comes to mind here...

It will be microplastics for future generations.

Lead, asbestos, microplastics, it's all the same thing regirgitated for future generations.

Viscious cycle..

Clearly evident and well researched in the literature.

2.6 and 4.3 feel signficant but 0.03 feels like a reach unless I am misunderstanding this.

Similarly as before with this I am wondering why this wouldn't be displayed as ~3.5%

I am wondering why they did not say 14% +/- 1.5%

You repeat steps over and over again to improve the solutions each time like how we wrote our narrative essay.

Its about how you think, question, and evaluate information for your own discipline.

What does this mean exactly?

What disciplines has its own methods besides Psychology?

I agree to this, sometimes when I read my research notes on something I don't have desire for it sounds not appealing.

I can agree on this because if I research something just cause I have to I won't be interested in learning and gather information about it.

★/ゴミ箱等、ワンクリックのものは、確認画面を必ず表示する

顔のアイコンはもう少し大きく

読み終わった日＝追加した日？

読書記録は、オフライン時はできない。

読書記録は自動で入れるか？ 読書記録の削除を可能とすること

削除したら、キャッシュからもクリアする。

ダウンロードできる量は団体ごとに決定できるようにする。行政によってモデルが異なるため。キャッシュクリア方法はどうするか検討する。1冊100MB*20冊を想定。団体で1G程度を想定。冊数ではなくサイズで判断する。途中の変更はあり。少なくされる可能性もあり。次ダウンロードするときに、サイズチェックを行う。

オンライン：ダウンロードした本＋お気に入り／オフライン：ダウンロードした本だけ

• オフラインのときは、ダウンロードした本だけが表示されます。読めるほんだけが表示されます。

お願い本を追加する

• Depende de <u>lei</u> do ente que instituiu o tributo dispor sobre compensação de créditos tributários vencidos e vincendos
• Logo, é possível constatar que a compensação não é um direito subjetivo pleno, tendo em vista que depende de previsão e regulamentação legal para que possa ser efetivo.
• Com isso, a lei pode optar por 2 sistemáticas: a) prevê no texto legal as condições e garantias para a compensação; b) atribuir à autoridade administrativa a competência para estipular garantias e condições para compensação.

What needs does this person have that the Savior can fill through the baptismal covenant? How can you emphasize the Savior's power during your teaching?

What promptings did you have from the Spirit as you were practicing this principle? How did you, or how can you, apply that into your practice?

When did you feel the Spirit most strongly during that demonstration? What is the Spirit prompting you to do to apply that into your practice?

What needs does this person have that the Savior can fill? How can they experience this through attending church?

1) Criado, através da EC 132/2023, o FNDR (Fundo Nacional de Desenvolvimento Regional).

2) Criado com o objetivo de reduzir as desigualdades <u>regionais</u> e <u>sociais</u>.

3) Os recursos do fundo são constituídos pela União e Estados/DF.

4) Servem-se para:

• Infraestrutura: obras, projetos e estudos;
• Potencial geração de emprego e renda (inclui-se subvenções);
• Ações de desenvolvimento tecnológico e científico.

5) Não previsão para que Municípios entreguem ou recebam recursos do FNDR

6) Não pode haver nenhuma restrição ao recebimento de recursos do FNDR.

What do you feel inspired to teach members to help them recognize the blessings they've received from coming to church?

What are blessings you've seen from applying love, share, and invite before or on your mission? How do you think that this could apply to the members you teach?

残す

お願い本を一番上に置く

読書記録ON／OFFは個人が設定する？団体で設定する？

メニューに入れるか？本棚に入れるか？

Sure it is:

It's not really a debate, HTML is a markup language [1], not a programming language

This is a false dichotomy, and untrue on two points (a) that HTML is "not a programming language", and (b) that the stance you have taken is not up for debate.

You're using the term "programming language" as shorthand to refer to the subset of languages more rigorously referred to as Turing-complete general-purpose programming languages.* There are programming languages outside this subset that no less have set membership with the larger "programming language" superset.

A programming language is a programming language in the sense that they have come to exist with the advent of the stored program computer. Though HTML and other markup languages are not** Turing-complete general-purpose programming languages, they are used every bit as much to describe a stored program as a language you might encounter when opening a file containing G-code "instructions" for controlling a CNC machine.

* We had a similar (but not the same) silly recurring argument in the 90s where people, at a loss for words to accurately capture their thoughts and grasping at whatever came to mind, argued that there were two distinct classes: "programming languages" and "scripting languages"—a category error arising from the same phenomenon of mistaking loose, off-the-cuff shorthand for The Real Idea Behind the Thing That's Involved Here

** No overlooking the fact that HTML is a proper superset of CSS, a provably Turing-complete (though not general-purpose) programming language—and JS, which is, of course, a true general-purpose programming language

(Originally drafted in response to https://news.ycombinator.com/item?id=46747778)

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He is told to have 6-12 months to live. Max and his wife go to a different clinic for holistic treatment, but they ghost them after the visit. He goes back to the original clinic and recieved paalliative care before he passes.

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He bullied his wife for 40 years, does not want CPR or respirator care. He yells at healthcare professionals and family for him being sick, blames medication. Eventually reveals he's afraid to die, particularly being buried alive. He receives medication that helps him calm down but dies of rising CO2 later on

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He's referred to hospice, responds very little to questions about death. He becomes bed bound, has routine visits to his home where he passes with his family.

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Ella has a chest film and expects lung cancer. She has lung tumor and states that if she becomes too ill, she wants to stop treatment. She receives DNR and is referred to hospice where the main goal is to relieve her suffering.

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Challenges the "progress" narrative by pointing out widespread poverty.

Acknowledges inequality within the imperial system despite claims of fairness.

本を探すのリンクを付与

OPEN一覧に遷移するリンクが欲しい

Blueのランダム

Openのみ

★再検討する

財団からの例外的なお知らせを想定している。→下の方でもいいのではないか？→上の方でOK。

本を探す画面は有効

Macaulay supports limited inclusion, but still assumes Indians are not yet equal

citation

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Trauma definition

aspirational :(

lmao what

Adjust this to 'meaningfully change' (as defined in the 'resolution criteria')

Clarify: the WELLBY with linear aggregation as in the definition above

Let's split up the answer boxes within this question to ask separately about the best use of currently collected data for these cases, and also ask what data should be collected in the future.

signpost more that we are talking about the very simple use of the WELLBY measure

Should be 'on WELLBY reliability and wellbeing measures' ... but also the folding box is still not ideal here -- better for this to link out to another page/subpage (open in new window)

More than just educationally, but also in society. If educators are unable to model resiliency and persistence, the question arises: how will the next generation learn those qualities? It is our responsibility as educators to push the next generation to be greater than we are today.

In my opinion, an educator's fit for the given role or school is not discussed nearly enough. If a person is not comfortable in some part of their occupational arena, the year can become a treacherous experience. A belief exists that one should be comfortable being uncomfortable. While that is aspirational, at some point one has to embrace something as comfortable if nothing else to have confidence that tomorrow is a new day.

Leadership in education is the secret sauce. In my time in the classroom, I’ve seen good teachers leave the classroom altogether because of questionable leadership. With that said, I’ve seen people who may not have been at the top of their class in education be brought under the umbrella of great leaders and have their entire perspective changed.

Chandra’s experiences are heartbreaking. She is the type of fighter that needs to be in education. Chandra’s lack of behavioral management is tough because she wants to give back so badly that she closes her eyes to problematic behaviors and the methods needed to fix them. She is the type of person who could potentially figure it out with time or when paired with a disciplinarian co-teacher. She also sounds like the type of person who could burn out very quickly. She could really go either way. In my opinion she has to find her niche’ and exhaust all options to accentuate those to her advantage. It may turn into a situatuation where she has to fake it till she makes it.

Everyone loves success stories, but humbling dialogues with your mentor or other educators about reflecting on negative endeavors are where true growth arises.

While reading this article, I was impressed by the choice of an architect as a professional stand-in for appraisal theory and archival appraisal. Terry Cook could’ve picked any profession really but an architect is such a great choice in relation to macro-appraisal because of how broad an architects social and physical dynamics and interactions can be and also how varied the purpose of a architect’s design can be. It really seems like the perfect choice for this subject and I kind of got hung up in the second part of this article trying to think of a comparable or better example that wouldn’t necessarily overlap with an architect directly. A novelist? Some sort of mass transit (commercial plane, train, bus, etc.) designer? It’s tough to come up with a topic that suits this subject as well as an architect.

land recognition or acknowledgement: - sdsu's attempt at land acknowledgement - (sdsu could do more) - going beyond post-colonial to decolonization

[Paper-level Aggregated] PMCID: PMC12221223

Evidence Type(s): Oncogenic, Predictive

Justification: Oncogenic: The text describes C>T transitions as characteristic of UV-induced mutations in melanoma, which are well-established features of cutaneous melanoma, indicating a role in tumorigenesis. Predictive: The identification of specific mutations, such as C>T transitions, suggests potential pharmacological targets for treatment in NF1Mut melanomas, indicating a predictive aspect for therapeutic response.

Gene→Variant (gene-first): NF1(4763):C>T

Genes: NF1(4763)

Variants: C>T

[Paper-level Aggregated] PMCID: PMC11551396

Evidence Type(s): Oncogenic, Predictive, Functional

Justification: Oncogenic: The text indicates that the exon 20 insertion variants (insASV and insSVD) exhibit enhanced catalytic rates and lower Km values compared to WT EGFR, suggesting their role in promoting cancer through increased activity. Predictive: The study evaluates the sensitivity of various EGFR mutations, including L858R and exon 20 insertions, to different inhibitors, indicating that the presence of specific mutations can predict the effectiveness of targeted therapies. Functional: The biochemical analysis of the variants, including kinetic studies and enzyme assays, demonstrates their functional characteristics, such as catalytic efficiency and inhibitor sensitivity, which are critical for understanding their role in cancer biology.

Gene→Variant (gene-first): EGFR(1956):C797 EGFR(1956):T790 EGFR(1956):T790M EGFR(1956):V948R TXK(7294):Glu4 EGFR(1956):L858R EGFR(1956):N771insSVD

Genes: EGFR(1956) TXK(7294)

Variants: C797 T790 T790M V948R Glu4 L858R N771insSVD

[Paper-level Aggregated] PMCID: PMC11272140

Evidence Type(s): Oncogenic, Prognostic, Functional

Justification: Oncogenic: The G2032R mutation is associated with acquired resistance to crizotinib and is shown to respond to taletrectinib, indicating its role in cancer progression. Prognostic: The response rates and progression-free survival data for patients with G2032R mutations suggest that this variant can provide prognostic information regarding treatment outcomes with taletrectinib. Functional: The text indicates that taletrectinib has activity against the G2032R mutation, suggesting that this variant has functional implications in the context of treatment response.

Gene→Variant (gene-first): ROS1(6098):G2032R NTRK1(4914):G2101A TXK(7294):L2026M TXK(7294):S1986F

Genes: ROS1(6098) NTRK1(4914) TXK(7294)

Variants: G2032R G2101A L2026M S1986F

[Paper-level Aggregated] PMCID: PMC11253285

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The text discusses the resistance mechanisms in tumor cells and the effects of specific treatments, indicating that the variants S3C and S4D may be involved in oncogenic processes related to PARPi resistance and tumor growth. Functional: The study assesses the functional impact of SRA737 and PARPi on cell growth and signaling pathways, demonstrating how these variants influence the response to treatment and cellular behavior.

Gene→Variant (gene-first): CHEK1(1111):S3C PARP1(142):S4D

Genes: CHEK1(1111) PARP1(142)

Variants: S3C S4D

[Paper-level Aggregated] PMCID: PMC10805385

Evidence Type(s): Oncogenic, Predictive

Justification: Oncogenic: The text indicates that HOXC10 is overexpressed in KRAS-mutant tumors, specifically mentioning the KRAS G12C variant, which is known to be associated with oncogenic activity in cancer. Predictive: The mention of robust HOXC10 expression in a patient-derived xenograft model with the KRAS G12C variant suggests that HOXC10 expression may predict response to treatment with MEK/BET inhibitors, indicating its potential as a predictive biomarker.

Gene→Variant (gene-first): KRAS(3845):G12C TP53(7157):G245V

Genes: KRAS(3845) TP53(7157)

Variants: G12C G245V

[Paper-level Aggregated] PMCID: PMC10690049

Evidence Type(s): Oncogenic, Predictive, Functional

Justification: Oncogenic: The text discusses the KRAS G12C and G12D mutations in the context of cancer cell lines, indicating that these variants are associated with tumorigenic properties, particularly highlighting the specific response of KRASG12C to treatment. Predictive: The evidence suggests that the presence of the KRAS G12C mutation predicts a positive response to the drug combination of MRTX849 and KPT9274, as indicated by the synergistic growth inhibition observed in KRASG12C-mutant cell lines. Functional: The study demonstrates the functional impact of KRAS G12C and G12D mutations on cell growth and drug response, showing that KRASG12C-mutant cells are sensitive to specific inhibitors while KRASG12D-mutant cells are not.

Gene→Variant (gene-first): KRAS(3845):G12C KRAS(3845):G12D

Genes: KRAS(3845)

Variants: G12C G12D

[Paper-level Aggregated] PMCID: PMC10618648

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The ERBB2 mutations V777L and G778A were identified in the tyrosine kinase domain, indicating their potential role in tumorigenesis. Functional: The T733I mutation was noted to be weakly transforming and associated with resistance to lapatinib, suggesting a functional impact on the behavior of the cancer cells.

Gene→Variant (gene-first): ERBB2(2064):G778A ERBB2(2064):V777L ERBB2(2064):T733I

Genes: ERBB2(2064)

Variants: G778A V777L T733I

[Paper-level Aggregated] PMCID: PMC10527017

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

Justification: Oncogenic: The HER2V777L and PIK3CAH1047R mutations are described as activating mutations that promote tumor formation and aggressive cancer characteristics, indicating their role in oncogenesis. Functional: The study demonstrates that the combination of HER2V777L and PIK3CAH1047R mutations enhances cellular migration and invasion, which are functional properties associated with metastatic cancer. Predictive: The findings suggest that the presence of HER2V777L and PIK3CAH1047R mutations can predict the effectiveness of specific drug combinations, such as neratinib plus trastuzumab deruxtecan, in treating breast cancer. Prognostic: The study indicates that the co-occurrence of HER2 and PIK3CA mutations is associated with accelerated tumor growth and metastasis, which can serve as a prognostic indicator for disease progression in breast cancer patients.

Gene→Variant (gene-first): ERBB2(2064):G776insYVMA ERBB2(2064):V777L PIK3CA(5290):H1047R

Genes: ERBB2(2064) PIK3CA(5290)

Variants: G776insYVMA V777L H1047R

[Paper-level Aggregated] PMCID: PMC10524391

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

Justification: Oncogenic: The presence of mutations such as EGFR T790M, L858R, and RET G810S is associated with resistance to targeted therapies, indicating their role in tumor progression and oncogenic potential. Predictive: The identification of specific mutations like EGFR T790M and RET G810S can predict resistance to therapies such as osimertinib, guiding treatment decisions. Functional: The text discusses resistance mutations that affect the function of EGFR and RET kinases, indicating their functional impact on therapeutic engagement and resistance mechanisms. Prognostic: The presence of mutations such as BRAF V600E and KRAS G12S, along with the response rates to treatment, suggests that these mutations may have prognostic implications for patient outcomes.

Gene→Variant (gene-first): EGFR(1956):C797S KRAS(3845):G12S RET(5979):G810S EGFR(1956):T790M BRAF(673):V600E RET(5979):V804E RET(5979):V804M RET(5979):V804M/E EGFR(1956):L747S EGFR(1956):L858R

Genes: EGFR(1956) KRAS(3845) RET(5979) BRAF(673)

Variants: C797S G12S G810S T790M V600E V804E V804M V804M/E L747S L858R

[Paper-level Aggregated] PMCID: PMC10390864

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

Justification: Functional: The study assessed the influence of various RAD51C missense mutations on HDR DNA repair activity, categorizing them as deleterious, hypomorphic, or neutral based on their effects on HDR scores, indicating their functional impact on DNA repair mechanisms. Oncogenic: The loss of RAD51C function promotes HR deficiency and sensitizes cells to cisplatin and olaparib, suggesting that variants affecting RAD51C function may contribute to oncogenic processes by impairing DNA repair and influencing drug sensitivity in cancer cells. Predictive: The study evaluated the sensitivity of cells with different RAD51C variants to cisplatin and olaparib, indicating that specific variants can predict responses to these drugs, which is crucial for therapeutic decision-making in cancer treatment. Prognostic: The correlation between RAD51C variant status and drug response (IC50 values) suggests that these variants may serve as prognostic markers for treatment outcomes in patients receiving cisplatin or olaparib.

Gene→Variant (gene-first): RAD51C(5889):16 A RAD51C(5889):C135Y RAD51C(5889):E94K RAD51C(5889):G130R RAD51C(5889):G302V RAD51C(5889):K131 RAD51C(5889):L138F RAD51C(5889):P21S RAD51C(5889):Q133E RAD51C(5889):R168 RAD51C(5889):R168G RAD51C(5889):R312 RAD51C(5889):R312W RAD51C(5889):T132I RAD51C(5889):T132R RAD51D(5892):T86I RAD51C(5889):V140E RAD51C(5889):p.Cys135Tyr RAD51C(5889):p.Thr132Ile RAD51C(5889):p.Val140Glu RAD51C(5889):A126T RAD51C(5889):D159N RAD51C(5889):G125V RAD51C(5889):G153D RAD51C(5889):G264S RAD51C(5889):G264V RAD51C(5889):G3R RAD51C(5889):L219S RAD51C(5889):Q143R RAD51C(5889):R214C RAD51C(5889):R258H RAD51C(5889):R366Q RAD51C(5889):T287A RAD51C(5889):V169A RAD51C(5889):p.Arg214Cys RAD51C(5889):p.Arg258His RAD51C(5889):p.Arg312Trp RAD51C(5889):p.Arg366Gln RAD51C(5889):p.Asp159Asn RAD51C(5889):p.Gln143Arg RAD51C(5889):p.Gly125Val RAD51C(5889):p.Gly153Asp RAD51C(5889):p.Gly264Ser RAD51C(5889):p.Gly264Val RAD51C(5889):p.Gly3Arg RAD51C(5889):p.Leu219Ser RAD51C(5889):p.Thr287Ala RAD51C(5889):p.Val169Ala RAD51C(5889):D109Y RAD51C(5889):G162E RAD51C(5889):L27P RAD51C(5889):S163R RAD51C(5889):T336P RAD51C(5889):p.Gly162Glu RAD51C(5889):p.Ser163Arg RAD51C(5889):p.Thr336Pro RAD51D(5892):p.Thr86Ile RAD51C(5889):A155E RAD51C(5889):C147Y RAD51(5888):D108G RAD51C(5889):D159Y RAD51C(5889):G306R RAD51C(5889):p.Ala155Glu RAD51(5888):p.Asp108Gly RAD51C(5889):p.Asp109Tyr RAD51C(5889):p.Asp159Tyr RAD51C(5889):p.Cys147Tyr RAD51C(5889):p.Gly306Arg RAD51C(5889):p.Pro21Ser RAD51C(5889):p.Glu94Lys RAD51C(5889):K131I

Genes: RAD51C(5889) RAD51D(5892) RAD51(5888)

Variants: 16 A C135Y E94K G130R G302V K131 L138F P21S Q133E R168 R168G R312 R312W T132I T132R T86I V140E p.Cys135Tyr p.Thr132Ile p.Val140Glu A126T D159N G125V G153D G264S G264V G3R L219S Q143R R214C R258H R366Q T287A V169A p.Arg214Cys p.Arg258His p.Arg312Trp p.Arg366Gln p.Asp159Asn p.Gln143Arg p.Gly125Val p.Gly153Asp p.Gly264Ser p.Gly264Val p.Gly3Arg p.Leu219Ser p.Thr287Ala p.Val169Ala D109Y G162E L27P S163R T336P p.Gly162Glu p.Ser163Arg p.Thr336Pro p.Thr86Ile A155E C147Y D108G D159Y G306R p.Ala155Glu p.Asp108Gly p.Asp109Tyr p.Asp159Tyr p.Cys147Tyr p.Gly306Arg p.Pro21Ser p.Glu94Lys K131I

[Paper-level Aggregated] PMCID: PMC10283448

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The presence of the ROS1-G2032R mutation is associated with crizotinib resistance in lung cancer, indicating its role in tumor progression and treatment failure. Functional: The study investigates the functional impact of various mutations, including E253Q, H178Q, H179Y, H555R, R143Q, and E171G, in the context of acquired resistance to repotrectinib, suggesting their potential roles in tumor biology and treatment response.

Gene→Variant (gene-first): CEBPA(1050):196_197insHP TP53(7157):E171G CCND3(896):E253Q ERBB2(2064):H178Q TP53(7157):H179Y RB1(5925):H555R ERBB2(2064):R143Q ROS1(6098):G2032R

Genes: CEBPA(1050) TP53(7157) CCND3(896) ERBB2(2064) RB1(5925) ROS1(6098)

Variants: 196_197insHP E171G E253Q H178Q H179Y H555R R143Q G2032R

[Paper-level Aggregated] PMCID: PMC10183391

Evidence Type(s): Oncogenic, Predictive, Functional

Justification: Oncogenic: The text describes a patient with stage IV NSCLC harboring the HER2 exon 19 p.L755P mutation, which is associated with the disease and indicates a potential role in tumorigenesis. Predictive: The evidence suggests that the presence of the HER2 exon 19 p.L755P mutation may predict the efficacy of osimertinib treatment, as the patient achieved a partial response after treatment. Functional: The text indicates that osimertinib has demonstrated activity against the HER2 exon 19 p.L755P mutation in both pre-clinical studies and in the reported case, suggesting a functional impact of the mutation on treatment response.

Gene→Variant (gene-first): ERBB2(2064):c.2262_2264delinsTCC ERBB2(2064):p.(L755P) ERBB2(2064):p.L755P

Genes: ERBB2(2064)

Variants: c.2262_2264delinsTCC p.(L755P) p.L755P

[Paper-level Aggregated] PMCID: PMC10161095

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The text describes how lysine-to-methionine mutations in histone H3 at lysine 27 (H3K27M) are associated with lethal childhood brain cancers, indicating that this variant contributes to tumorigenesis. Functional: The evidence shows that H3K27M mutations alter chromatin remodeling and affect protein levels of the SWI/SNF complex, demonstrating a functional impact on cellular processes related to cancer.

Gene→Variant (gene-first): H3-3B(3021):lysine 27 PBRM1(55193):lysine-to-methionine

Genes: H3-3B(3021) PBRM1(55193)

Variants: lysine 27 lysine-to-methionine

[Paper-level Aggregated] PMCID: PMC10082285

Evidence Type(s): Predictive, Prognostic, Oncogenic

Justification: Predictive: The study involves patients with EGFR-mutated NSCLC, specifically mentioning the L858R variant, and evaluates the efficacy of osimertinib, indicating that the presence of this mutation can predict response to treatment. Prognostic: The study assesses disease-free survival (DFS) and overall survival in patients with the L858R variant, suggesting that this mutation may have implications for patient outcomes. Oncogenic: The mention of the L858R mutation in the context of EGFR-mutated NSCLC indicates its role in driving cancer development, classifying it as an oncogenic variant.

Gene→Variant (gene-first): EGFR(1956):L858R

Genes: EGFR(1956)

Variants: L858R

[Paper-level Aggregated] PMCID: PMC10015977

Evidence Type(s): Prognostic, Oncogenic, Functional

Justification: Prognostic: The text indicates that SF3B1 mutations, particularly K700E, are associated with a favorable prognosis in myelodysplastic syndromes (MDS), as evidenced by superior overall survival (OS) rates compared to SF3B1 wild-type patients. Oncogenic: The presence of SF3B1 mutations, including K700E and R625C, is implicated in the pathogenesis of myelodysplastic syndromes, suggesting their role as oncogenic drivers in this context. Functional: The analysis of splicing events and gene expression profiles between K700E and non-K700E SF3B1 mutations indicates functional differences that may impact disease characteristics and outcomes in MDS.

Gene→Variant (gene-first): SETBP1(26040):E862K SF3B1(23451):K700E SF3B1(23451):R625C SF3B1(23451):K666 SF3B1(23451):K700 SF3B1(23451):R625

Genes: SETBP1(26040) SF3B1(23451)

Variants: E862K K700E R625C K666 K700 R625

[Paper-level Aggregated] PMCID: PMC10011885

Evidence Type(s): Oncogenic, Predictive, Functional

Justification: Oncogenic: The BRAF V600E mutation is identified as a significant alteration in metastatic colorectal cancer (mCRC) and is associated with the disease's progression and treatment resistance, indicating its role in oncogenesis. Predictive: Early ctDNA dynamics, including changes in BRAF V600E levels, were shown to predict treatment efficacy, with significant correlations between ctDNA levels and clinical outcomes such as progression-free survival (PFS) and overall survival (OS). Functional: The emergence of KRAS and NRAS mutations, including specific variants like KRAS Q61H and G13D, was linked to treatment resistance, suggesting that these mutations have functional implications in the context of therapy response.

Gene→Variant (gene-first): KDR(3791):A163G KRAS(3845):G12D KRAS(3845):G12N KRAS(3845):G13D KRAS(3845):Q61H NRAS(4893):Q61L SLTM(79811):R106H BRAF(673):V600E NRAS(4893):G13C

Genes: KDR(3791) KRAS(3845) NRAS(4893) SLTM(79811) BRAF(673)

Variants: A163G G12D G12N G13D Q61H Q61L R106H V600E G13C

[Paper-level Aggregated] PMCID: PMC9900321

Evidence Type(s): Oncogenic, Predictive

Justification: Oncogenic: The passage indicates that Gly-to-Asp mutations (KRASG12D) are commonly found in pancreatic ductal adenocarcinoma (PDAC), suggesting that this variant is associated with the development of cancer. Predictive: The text discusses the efficacy of a small-molecule KRASG12D inhibitor, MRTX1133, in models with KRASG12D mutations, indicating that the presence of this variant can predict the response to targeted therapy.

Gene→Variant (gene-first): KRAS(3845):Gly-to-Asp

Genes: KRAS(3845)

Variants: Gly-to-Asp

[Paper-level Aggregated] PMCID: PMC9859631

Evidence Type(s): Oncogenic, Predictive, Functional

Justification: Oncogenic: The text describes various ERBB2 alterations, including ERBB2DeltaEx16 variants, which are suggested to play a role in resistance to targeted therapies, indicating their potential oncogenic nature. Predictive: The presence of specific mutations such as L858R, L755S, D769Y, and others in the context of treatment resistance suggests that these variants may predict response to therapies and disease progression. Functional: The identification of multiple ERBB2 alterations and their association with resistance mechanisms implies that these variants may have functional consequences on the gene's activity and its role in cancer progression.

Gene→Variant (gene-first): SLTM(79811):D1288N L1195I SLTM(79811):L1195V SLTM(79811):Y1230H ERBB2(2064):c.1899-936_1946+520del ERBB2(2064):D769Y ERBB2(2064):L755S EGFR(1956):L858R ERBB2(2064):c.1899-32_1909del ERBB2(2064):c.1899-2A>G ERBB2(2064):c.1899-880_1946+761del

Genes: SLTM(79811) ERBB2(2064) EGFR(1956)

Variants: D1288N L1195I L1195V Y1230H c.1899-936_1946+520del D769Y L755S L858R c.1899-32_1909del c.1899-2A>G c.1899-880_1946+761del

[Paper-level Aggregated] PMCID: PMC9837058

Evidence Type(s): Oncogenic, Functional, Predictive

Justification: Oncogenic: The text discusses multiple mutations (e.g., H1047R, G1049R, M1043L, N1068fs) that are frequently observed in cancer and describes their role in activating the PI3K pathway, indicating their oncogenic potential. Functional: The evidence describes how specific mutations (H1047R, G1049R, M1043L) lead to increased ATPase activity and enhanced membrane binding, demonstrating their functional impact on the PI3K enzyme activity. Predictive: The identification of specific mutations associated with increased membrane binding and PI3K activity suggests that these mutations could be used to predict the behavior of tumors and their response to therapies targeting the PI3K pathway.

Gene→Variant (gene-first): PIK3CA(5290):D915N PIK3CA(5290):E726K PIK3CA(5290):G1049R PIK3CA(5290):H1047R PIK3CA(5290):H1047R/L PIK3CA(5290):M1043L PIK3CA(5290):M1043L/I PIK3CA(5290):N1044K PIK3CA(5290):N1068fs PIK3CA(5290):M1043I/L PIK3CA(5290):G106V PIK3CA(5290):G118D PIK3CA(5290):N345K PIK3CA(5290):His1047 PIK3CA(5290):Met1043

Genes: PIK3CA(5290)

Variants: D915N E726K G1049R H1047R H1047R/L M1043L M1043L/I N1044K N1068fs M1043I/L G106V G118D N345K His1047 Met1043

[Paper-level Aggregated] PMCID: PMC9468105

Evidence Type(s): Predisposing, Oncogenic, Prognostic

Justification: Predisposing: The text describes gliomas arising in patients with a heterozygous germline mutation in NF1, indicating a genetic predisposition to tumor development. Oncogenic: The presence of somatic mutations and inactivation of the wild-type NF1 allele, along with the mention of specific mutations like p.R1276* and c.4110 + 2 T > G, supports the role of these variants in tumorigenesis. Prognostic: Kaplan-Meier survival analysis indicates that patients with NF1-associated gliomas have inferior outcomes, suggesting that the genetic alterations may have prognostic implications for patient survival.

Gene→Variant (gene-first): NF1(4763):c.4110 + 2 T > G NF1(4763):p.R1276* BRAF(673):p.V600E

Genes: NF1(4763) BRAF(673)

Variants: c.4110 + 2 T > G p.R1276* p.V600E

[Paper-level Aggregated] PMCID: PMC9441062

Evidence Type(s): Oncogenic, Predictive, Prognostic

Justification: Oncogenic: The presence of EGFR mutations, including L858R and G719C/S768I, is associated with oncogenic activity in NSCLC, as they are known to drive tumorigenesis. Predictive: The identified second-site EGFR mutations, such as T790M and C797S/G, are recognized as predictive markers for resistance to EGFR-TKIs, indicating their role in treatment response. Prognostic: The study reports that certain genetic alterations, including bypass pathway mutations and co-mutations of TP53 and RB1, are associated with significantly shorter progression-free survival (PFS) in patients treated with EGFR-TKIs, highlighting their prognostic significance.

Gene→Variant (gene-first): EGFR(1956):C797S/G EGFR(1956):L718V/Q EGFR(1956):T790M EGFR(1956):G719C EGFR(1956):L858R EGFR(1956):S768I

Genes: EGFR(1956)

Variants: C797S/G L718V/Q T790M G719C L858R S768I

[Paper-level Aggregated] PMCID: PMC9402235

Evidence Type(s): Oncogenic, Diagnostic, Predictive

Justification: Oncogenic: The de novo pathogenic variant NM_005648.4(ELOC):c.236A>G (p.Tyr79Cys) is associated with VHL-independent renal tumorigenesis and has been previously described as a somatic variant in renal cell carcinomas (RCCs) without VHL inactivation, indicating its role in cancer development. Diagnostic: The identification of the NM_005648.4(ELOC):c.236A>G (p.Tyr79Cys) variant in a proband with VHL disease suggests that genetic testing for ELOC variants should be performed in individuals with suspected VHL disease, thereby aiding in diagnosis. Predictive: The presence of the NM_005648.4(ELOC):c.236A>G (p.Tyr79Cys) variant has implications for predicting the development of VHL disease and associated renal tumors, as it mimics the effects of pVHL deficiency on hypoxic signaling.

Gene→Variant (gene-first): HIF1A(3091):Tyr79 HIF1A(3091):Y79 HIF1A(3091):c.236A>G HIF1A(3091):p.Tyr79Cys ELOC(6921):c.261_272del RET(5979):c.274G>A ELOC(6921):c.311T>A KRT7(3855):c.74A>T KRT7(3855):p.Asp25Val VAV1(7409):p.Glu92Lys ELOC(6921):p.Leu104Gln ELOC(6921):p.Thr88_Pro91del

Genes: HIF1A(3091) ELOC(6921) RET(5979) KRT7(3855) VAV1(7409)

Variants: Tyr79 Y79 c.236A>G p.Tyr79Cys c.261_272del c.274G>A c.311T>A c.74A>T p.Asp25Val p.Glu92Lys p.Leu104Gln p.Thr88_Pro91del

[Paper-level Aggregated] PMCID: PMC9398166

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

Justification: Oncogenic: The text discusses various ALK mutations, including G1202R and L1196M, which are described as major resistance mechanisms to ALK inhibitors, indicating their role in oncogenesis. Functional: The evidence describes the biochemical characterization of TPX-0131's potency against various ALK mutations, demonstrating its functional ability to inhibit both wild-type and mutant ALK, including resistance mutations. Predictive: The text indicates that TPX-0131 was designed to avoid resistance mutations and shows significant potency against them, suggesting its potential predictive value for treatment outcomes in patients with these mutations. Prognostic: The discussion of TPX-0131's efficacy against a range of ALK mutations, including those associated with resistance, implies that the presence of these mutations could influence treatment response and patient prognosis.

Gene→Variant (gene-first): ALK(238):C1156Y ALK(238):D1203N ALK(238):E1210K ALK(238):F1174C ALK(238):F1174L ALK(238):F1174S ALK(238):F1245C ALK(238):G1202 ALK(238):G1202R ALK(238):G1269A ALK(238):G1269S ALK(238):I1171N ALK(238):L1152P ALK(238):L1152R ALK(238):L1196M ALK(238):L1198F ALK(238):R1275Q ALK(238):S1206C ALK(238):S1206R ALK(238):T1151-L1152 insT ALK(238):T1151M ALK(238):V1180L ALK(238):I1171N/S ALK(238):L1204V ALK(238):S/T ALK(238):L1198

Genes: ALK(238)

Variants: C1156Y D1203N E1210K F1174C F1174L F1174S F1245C G1202 G1202R G1269A G1269S I1171N L1152P L1152R L1196M L1198F R1275Q S1206C S1206R T1151-L1152 insT T1151M V1180L I1171N/S L1204V S/T L1198

[Paper-level Aggregated] PMCID: PMC9365372

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The text indicates that patients with the EGFR T790M mutation showed responses to treatment with abivertinib, suggesting that the presence of this variant can predict treatment efficacy. Oncogenic: The T790M variant is associated with resistance to EGFR inhibitors and is implicated in the progression of non-small cell lung cancer (NSCLC), indicating its role in oncogenesis.

Gene→Variant (gene-first): EGFR(1956):T790M EGFR(1956):Thr790Met

Genes: EGFR(1956)

Variants: T790M Thr790Met

[Paper-level Aggregated] PMCID: PMC9338780

Evidence Type(s): Predictive, Oncogenic, Prognostic

Justification: Predictive: The text discusses the approval of dabrafenib plus trametinib for treatment of BRAF V600E-mutant anaplastic thyroid cancer, indicating that the presence of the V600E mutation predicts a positive response to this therapy. Oncogenic: The BRAF V600E mutation is implicated in the pathogenesis of anaplastic thyroid cancer, suggesting its role as an oncogenic driver in this disease. Prognostic: The updated results indicate that patients with BRAF V600E-mutant ATC experienced improved long-term survival with the treatment, suggesting that the mutation may serve as a prognostic marker for treatment outcomes.

Gene→Variant (gene-first): BRAF(673):V600E

Genes: BRAF(673)

Variants: V600E

[Paper-level Aggregated] PMCID: PMC8887939

Evidence Type(s): Prognostic, Oncogenic

Justification: Prognostic: The text provides data on overall response rates (ORR), median duration of response (DoR), and median progression-free survival (PFS) associated with specific mutations, indicating their potential to predict clinical outcomes. Oncogenic: The mention of specific mutations (A775dupYVMA and G776delinsVC) in the context of their frequency and associated clinical outcomes suggests a role in tumorigenesis.

Gene→Variant (gene-first): ERBB2(2064):A775dupYVMA ERBB2(2064):G776delinsVC

Genes: ERBB2(2064)

Variants: A775dupYVMA G776delinsVC

[Paper-level Aggregated] PMCID: PMC8881279

Evidence Type(s): Oncogenic, Functional, Predictive

Justification: Oncogenic: The evidence indicates that the ERBB2 E401G variant enhances C-terminal phosphorylation and increases invasive capacity in cancer cells, suggesting its role in promoting oncogenic properties. Functional: The study demonstrates that ERBB2 E401G has functional properties similar to known activating mutations, affecting dimerization and phosphorylation mechanisms, which are critical for its role in signaling pathways. Predictive: The identification of the ERBB2 E401G variant as a variant of unknown significance (VUS) and its evaluation through computational tools predicting pathogenicity suggest its potential as a predictive marker for therapeutic targeting.

Gene→Variant (gene-first): MYC(4609):1157A > G FANCC(2176):E401G ERBB2(2064):D845A TP53(7157):E321G ERBB2(2064):S310F FANCC(2176):p.(E401G)

Genes: MYC(4609) FANCC(2176) ERBB2(2064) TP53(7157)

Variants: 1157A > G E401G D845A E321G S310F p.(E401G)

[Paper-level Aggregated] PMCID: PMC8727519

Evidence Type(s): Oncogenic, Predictive, Prognostic

Justification: Oncogenic: The presence of the EGFR L858R and T790M variants in the patient's lung adenocarcinoma indicates their role in tumorigenesis and resistance to treatment, supporting their classification as oncogenic. Predictive: The identification of the T790M variant suggests a potential resistance mechanism to first-generation EGFR tyrosine kinase inhibitors, indicating its predictive value for treatment response. Prognostic: The patient's progression-free survival interval of more than 11 months after switching to osimertinib suggests that the presence of the T790M variant may have prognostic implications for treatment outcomes in NSCLC.

Gene→Variant (gene-first): EGFR(1956):L858R EGFR(1956):T790M

Genes: EGFR(1956)

Variants: L858R T790M

[Paper-level Aggregated] PMCID: PMC8700411

Evidence Type(s): Oncogenic, Predictive, Prognostic

Justification: Oncogenic: The text describes EGFR exon 20 insertion mutations, including G770 equivalence, as being associated with sensitivity to specific EGFR TKIs, indicating their role in driving cancer progression. Predictive: The evidence suggests that patients with EGFR exon 20 insertion mutations, particularly those with G770 equivalence, can be predicted to respond to certain EGFR TKIs, such as afatinib and dacomitinib, based on preclinical and clinical data. Prognostic: The clinical outcomes reported for patients with EGFR exon 20 insertion mutations indicate that these mutations can influence treatment responses and outcomes, suggesting a prognostic role in advanced lung cancers.

Gene→Variant (gene-first): EGFR(1956):D770 EGFR(1956):G770 EGFR(1956):Y764insFQEA EGFR(1956):D770_N771insSVD EGFR(1956):V769dupASV

Genes: EGFR(1956)

Variants: D770 G770 Y764insFQEA D770_N771insSVD V769dupASV

[Paper-level Aggregated] PMCID: PMC8688876

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

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

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

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

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

[Paper-level Aggregated] PMCID: PMC8453302

Evidence Type(s): Oncogenic, Prognostic

Justification: Oncogenic: The G292R variant in HER2 is associated with a complete response to treatment, indicating its role in driving cancer progression and treatment response in metastatic cervical adenocarcinoma. Prognostic: The mention of a progression-free survival of 25 months in a patient with the G292R variant suggests that this variant may have implications for predicting treatment outcomes in cervical cancer.

Gene→Variant (gene-first): ERBB2(2064):G292R

Genes: ERBB2(2064)

Variants: G292R

[Paper-level Aggregated] PMCID: PMC8307492

Evidence Type(s): Predictive, Prognostic, Oncogenic

Justification: Predictive: The text discusses the association of specific EGFR mutations, such as L858R and exon 19 deletions, with overall survival (OS) outcomes in patients treated with first-line EGFR inhibitors, indicating their predictive value for treatment response. Prognostic: The analysis of overall survival (OS) based on different EGFR mutation subclasses, including L858R and uncommon actionable variants, demonstrates their prognostic significance in determining patient outcomes. Oncogenic: The presence of EGFR mutations, including L858R and T790M, is associated with non-small-cell lung cancer (NSCLC), indicating their role in oncogenesis.

Gene→Variant (gene-first): EGFR(1956):G719S EGFR(1956):L858R EGFR(1956):L861Q EGFR(1956):T790M EGFR(1956):L861X

Genes: EGFR(1956)

Variants: G719S L858R L861Q T790M L861X

[Paper-level Aggregated] PMCID: PMC8285406

Evidence Type(s): Oncogenic, Predictive, Prognostic

Justification: Oncogenic: The text describes several FGFR mutations, including N546K, K656E, S249C, and others, as oncogenic mutations that exhibit significant transforming activities in various cancers, indicating their role in tumorigenesis. Predictive: The evidence indicates that specific FGFR mutations, such as N549D/K and K650M/N, show different sensitivities to FGFR inhibitors, suggesting that these variants can predict the response to targeted therapies. Prognostic: The text mentions that patients with FGFR mutations and fusions had a higher overall response rate to FGFR TKIs compared to those with amplifications, indicating that these mutations may serve as prognostic markers for treatment outcomes.

Gene→Variant (gene-first): PIK3CA(5290):E542K PIK3CA(5290):E545K PIK3CA(5290):H1047R KRAS(3845):G12V FGFR1(2260):N546K FGFR2(2263):N549D/K FGFR3(2261):G370C FGFR3(2261):G380E/R FGFR3(2261):K650E/M FGFR2(2263):K659E FGFR2(2263):N549H FGFR3(2261):R248C FGFR3(2261):S249C TACC1(6867):S342F FGFR3(2261):S371C FGFR2(2263):W290C FGFR3(2261):Y373C FGFR3(2261):K650E FGFR3(2261):K650M FGFR3(2261):K650N FGFR2(2263):N549K FGFR2(2263):K656 FGFR2(2263):K656E/M FGFR2(2263):N549 FGFR2(2263):N549D/H FGFR1(2260):K656E FGFR2(2263):S252W FGFR2(2263):V550L FGFR4(2264):N535K EGFR(1956):R248H

Genes: PIK3CA(5290) KRAS(3845) FGFR1(2260) FGFR2(2263) FGFR3(2261) TACC1(6867) FGFR4(2264) EGFR(1956)

Variants: E542K E545K H1047R G12V N546K N549D/K G370C G380E/R K650E/M K659E N549H R248C S249C S342F S371C W290C Y373C K650E K650M K650N N549K K656 K656E/M N549 N549D/H K656E S252W V550L N535K R248H

[Paper-level Aggregated] PMCID: PMC8255005

Evidence Type(s): Prognostic, Oncogenic, Functional

Justification: Prognostic: The text states that FLT3 mutations are associated with poor prognosis in acute myeloid leukemia (AML), indicating that the presence of these mutations can provide information about the likely outcome of the disease. Oncogenic: The mention of FLT3 mutations, including D835 and F691L, as common genetic alterations in AML suggests that these variants contribute to the development of cancer. Functional: The text discusses the resistance of FLT3 mutations (specifically F691L and D835Y) to FLT3 inhibitors and the mechanisms by which KX2-391 overcomes this resistance, indicating a functional role of these mutations in drug response.

Gene→Variant (gene-first): FLT3(2322):D835 FLT3(2322):D835Y FLT3(2322):F691 FLT3(2322):F691L

Genes: FLT3(2322)

Variants: D835 D835Y F691 F691L

[Paper-level Aggregated] PMCID: PMC8203843

Evidence Type(s): Oncogenic, Predictive

Justification: Oncogenic: The IDH1 R132H mutation is associated with glioma and is known to induce homologous recombination defects, which contributes to the oncogenic process in these tumors. Predictive: The study demonstrates that the presence of the IDH1 R132H mutation influences sensitivity to PARP inhibitors, indicating that this variant can predict treatment response in glioma patients.

Gene→Variant (gene-first): IDH1(3417):R132H

Genes: IDH1(3417)

Variants: R132H

[Paper-level Aggregated] PMCID: PMC8078423

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The study evaluates the efficacy of encorafenib plus cetuximab in patients with BRAFV600E-mutant metastatic colorectal cancer, indicating that the presence of the BRAFV600E variant predicts a response to this treatment regimen. Oncogenic: The mention of BRAFV600E as a mutation in metastatic colorectal cancer suggests that it plays a role in the oncogenesis of this cancer type, as it is a known driver mutation associated with tumor development.

Gene→Variant (gene-first): BRAF(673):BRAFV600E BRAF(673):V600E

Genes: BRAF(673)

Variants: BRAFV600E V600E

[Paper-level Aggregated] PMCID: PMC8077124

Evidence Type(s): Oncogenic, Functional, Prognostic

Justification: Oncogenic: The FGFR1 p.K656E mutation is described as a known hotspot mutation that is both activating and transforming, indicating its role in tumorigenesis. Functional: The FGFR1 p.V561M mutation is characterized as a gatekeeper mutation that imparts resistance to FGFR inhibitors, suggesting a functional impact on treatment response. Prognostic: The text mentions that pilomyxoid astrocytomas are characterized by shorter survival and high recurrence rates, indicating that the presence of these mutations may have implications for patient prognosis.

Gene→Variant (gene-first): FGFR1(2260):c.1681G>A FGFR1(2260):c.1966A>G FGFR1(2260):p.K656E FGFR1(2260):p.V561M IDH1(3417):p.R132H BRAF(673):p.V600E

Genes: FGFR1(2260) IDH1(3417) BRAF(673)

Variants: c.1681G>A c.1966A>G p.K656E p.V561M p.R132H p.V600E

[Paper-level Aggregated] PMCID: PMC8040738

Evidence Type(s): Oncogenic, Predictive, Prognostic

Justification: Oncogenic: The presence of the BRAF p.T599dup mutation in the tumor is associated with tumor growth and progression, indicating its role in oncogenesis. Predictive: The identification of BRAF alterations, including p.T599dup, may assist clinicians in determining alternative targeted treatment strategies, suggesting its predictive value for treatment response. Prognostic: The report discusses the poor prognosis associated with many central nervous system diagnoses, indicating that BRAF mutations may have implications for patient outcomes.

Gene→Variant (gene-first): BRAF(673):V600E BRAF(673):p.T599dup BRAF(673):p.V600E NA:p.T599dup BRAF

Genes: BRAF(673) NA

Variants: V600E p.T599dup p.V600E p.T599dup BRAF

[Paper-level Aggregated] PMCID: PMC8033310

Evidence Type(s): Oncogenic, Predictive, Prognostic

Justification: Oncogenic: The presence of PIK3CA mutations (E545K and H1047R) in TNBC cell lines was associated with increased cell proliferation and decreased apoptosis, indicating that these mutations contribute to tumorigenesis. Predictive: The study suggests that PIK3CA mutations may alter the sensitivity of TNBC cells to chemotherapy, as cells with these mutations showed decreased sensitivity to epirubicin treatment. Prognostic: The frequency of PIK3CA mutations in patients with TNBC and their association with clinical outcomes, such as chemotherapy response and recurrence, indicates that these mutations may have prognostic implications for patient outcomes.

Gene→Variant (gene-first): PIK3CA(5290):E545K PIK3CA(5290):H1047R

Genes: PIK3CA(5290)

Variants: E545K H1047R

[Paper-level Aggregated] PMCID: PMC8008494

Evidence Type(s): Functional, Oncogenic, Predictive

Justification: Functional: The text describes a functional assay (HDR) that evaluates the impact of various variants on protein function, indicating that certain variants resulted in loss of function or maintained functionality based on their HDR scores. Oncogenic: The mention of variants being associated with probabilities of pathogenicity >0.99 suggests that these variants may contribute to cancer development, indicating their potential oncogenic nature. Predictive: The text discusses the ability of certain variants to influence sensitivity to PARP inhibitors, which can be used to predict treatment responses in BRCA2-deficient cell lines.

Gene→Variant (gene-first): NA:2619 from Trp to Gly BRCA2(675):2723 from Asp to Asn APRT(353):7522G>A APRT(353):7807G>T APRT(353):7874G>A APRT(353):7879A>G NA:Leu3180 APRT(353):Phe/Asn APRT(353):c.7522G>C BRCA2(675):c.7880T>A BRCA2(675):c.9370A>C BRCA2(675):c.9371A>T BRCA2(675):c.9539T>C BRCA2(675):p.Ala2603Ser BRCA2(675):p.Arg2625Lys BRCA2(675):p.Asn3124His APRT(353):p.Gly2508Arg BRCA2(675):p.Gly2508Ser BRCA2(675):p.Ile2627Val BRCA2(675):c.8723T>G BRCA2(675):c.8905G>A BRCA2(675):p.Val2908Gly BRCA2(675):p.Val2969Met

Genes: NA BRCA2(675) APRT(353)

Variants: 2619 from Trp to Gly 2723 from Asp to Asn 7522G>A 7807G>T 7874G>A 7879A>G Leu3180 Phe/Asn c.7522G>C c.7880T>A c.9370A>C c.9371A>T c.9539T>C p.Ala2603Ser p.Arg2625Lys p.Asn3124His p.Gly2508Arg p.Gly2508Ser p.Ile2627Val c.8723T>G c.8905G>A p.Val2908Gly p.Val2969Met

[Paper-level Aggregated] PMCID: PMC7820803

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The study demonstrates that the p.Ala636Pro variant leads to a significant loss of MSH2 function, as evidenced by the inability of cells expressing this variant to restore sensitivity to 6-thioguanine, indicating a functional impairment in mismatch repair. Oncogenic: The p.Ala636Pro variant is described as a pathogenic founder allele, suggesting its role in contributing to cancer predisposition, particularly in the context of MMR deficiency associated with Lynch syndrome.

Gene→Variant (gene-first): MSH2(4436):p.Ala636Pro

Genes: MSH2(4436)

Variants: p.Ala636Pro

[Paper-level Aggregated] PMCID: PMC7785563

Evidence Type(s): Oncogenic, Predisposing

Justification: Oncogenic: The text indicates that 90% of the cases harbored the IDH1-R132H mutation, which is associated with conventional supratentorial IDH-mutant astrocytomas, suggesting its role in tumorigenesis. Predisposing: The mention of a personal and family history of colorectal cancer in case no. 10, along with the identification of germline mutations in MMR genes, suggests a predisposition to cancer in these cases.

Gene→Variant (gene-first): IDH1(3417):R132H

Genes: IDH1(3417)

Variants: R132H

[Paper-level Aggregated] PMCID: PMC7612475

Evidence Type(s): Oncogenic, Functional, Predictive

Justification: Oncogenic: The SF3B1K700E mutation is associated with a BRCA-like cellular phenotype that compromises homologous recombination (HR) and increases sensitivity to DNA damaging agents, indicating its role in cancer development. Functional: The SF3B1K700E mutation affects the ability of cells to resolve recombination intermediates and induces unscheduled R-loops, leading to stalled replication forks and reduced replication fork protection, demonstrating a functional impact on DNA repair mechanisms. Predictive: The presence of the SF3B1K700E mutation predicts increased sensitivity to PARP inhibitors and other chemotherapeutic agents, suggesting its potential as a therapeutic target in cancer treatment.

Gene→Variant (gene-first): RNASEH1(246243):D210N SF3B1(23451):K700E

Genes: RNASEH1(246243) SF3B1(23451)

Variants: D210N K700E

[Paper-level Aggregated] PMCID: PMC7612117

Evidence Type(s): Oncogenic, Functional, Predisposing

Justification: Oncogenic: The evidence indicates that the BRCA1 p.L1363P variant disrupts the interaction with PALB2, leads to embryonic lethality, and accelerates the development of Trp53-deficient mammary tumors, suggesting its role in cancer development. Functional: The study demonstrates that Brca1 p.L1363P impairs homologous recombination repair (HRR) and affects BRCA1-PALB2 interaction, indicating a functional defect associated with this variant. Predisposing: The findings suggest that the BRCA1 p.L1363P variant increases the risk of developing breast cancer, as it leads to tumor formation in a mouse model.

Gene→Variant (gene-first): BRCA1(672):4220T>C TP53BP1(7158):p.L1363P BRCA1(672):p.L1407P TP53BP1(7158):L1363P BRCA1(672):leucine to proline

Genes: BRCA1(672) TP53BP1(7158)

Variants: 4220T>C p.L1363P p.L1407P L1363P leucine to proline

[Paper-level Aggregated] PMCID: PMC7611203

Evidence Type(s): Oncogenic, Predictive, Predisposing

Justification: Oncogenic: The text discusses multiple pathogenic mutations, including BRCA1 and BRCA2 variants, which are known to be associated with an increased risk of breast and ovarian cancer, indicating their oncogenic potential. Predictive: The mention of neoantigens derived from pathogenic mutations being likely presented by HLA class I complexes suggests that these mutations can be used to predict immune responses, which is a predictive aspect in the context of cancer treatment. Predisposing: The identification of common founder mutations such as BRCA1:c.185delAG and BRCA2:c.6174delT indicates that these variants predispose individuals to developing certain cancers, thus classifying them as predisposing mutations.

Gene→Variant (gene-first): BRCA1(672):c.185delAG BRCA1(672):c.5266dupC BRCA2(675):c.5946delT BRCA2(675):c.6174delT BRCA1(672):c.68_69delAG BRCA1(672):p.C61S BRCA1(672):p.M1I

Genes: BRCA1(672) BRCA2(675)

Variants: c.185delAG c.5266dupC c.5946delT c.6174delT c.68_69delAG p.C61S p.M1I

[Paper-level Aggregated] PMCID: PMC7568619

Evidence Type(s): Oncogenic, Predictive

Justification: Oncogenic: The L1196Q mutation in ALK was identified as a secondary mutation associated with resistance to alectinib, indicating its role in tumor progression and treatment failure. Predictive: The identification of the L1196Q mutation guided the treatment decision to prescribe ceritinib, which resulted in a partial response, suggesting its predictive value for treatment outcomes.

Gene→Variant (gene-first): ALK(238):L1196Q

Genes: ALK(238)

Variants: L1196Q

[Paper-level Aggregated] PMCID: PMC7545690

Evidence Type(s): Prognostic, Predictive

Justification: Prognostic: The variant rs3786362 in TYMS is associated with reduced progression-free survival (PFS) and overall survival (OS) in mCRC patients, indicating its potential as a prognostic marker for patient outcomes. Predictive: The study suggests that rs3786362 may serve as a predictive biomarker for survival in specific subgroups of mCRC patients, as it correlates with treatment response and survival outcomes based on genotype.

Gene→Variant (gene-first): FTCD(10841):rs10432965 FOLH1(2346):rs369803 TYMS(7298):rs3786362 SLC46A1(113235):rs4795436

Genes: FTCD(10841) FOLH1(2346) TYMS(7298) SLC46A1(113235)

Variants: rs10432965 rs369803 rs3786362 rs4795436

[Paper-level Aggregated] PMCID: PMC7499606

Evidence Type(s): Oncogenic, Prognostic

Justification: Oncogenic: The TP53 Y220C missense mutation is described as a "deleterious somatic mutation," indicating its role in promoting cancer development. Prognostic: The patient's response to various treatments, including the combination therapy, suggests that the presence of the Y220C mutation may influence treatment outcomes and disease progression.

Gene→Variant (gene-first): TP53(7157):Y220C

Genes: TP53(7157)

Variants: Y220C

[Paper-level Aggregated] PMCID: PMC7472556

Evidence Type(s): Oncogenic, Diagnostic, Prognostic

Justification: Oncogenic: The text discusses the upregulation of NRG1 in response to hormone therapy and its association with promoting resistance to androgen deprivation therapy (ADT), indicating a role in cancer progression. Diagnostic: The detection of NRG1 expression using an immunohistochemical assay in patients with localized prostate cancer suggests its potential use as a diagnostic marker for assessing treatment response. Prognostic: The correlation between NRG1 expression and patient outcomes, particularly in relation to ADT treatment, implies that NRG1 levels may serve as a prognostic indicator for treatment efficacy in prostate cancer.

Gene→Variant (gene-first): RET(5979):Q8 NRG1(3084):S6 KAT2B(8850):S7 KAT2B(8850):S7C

Genes: RET(5979) NRG1(3084) KAT2B(8850)

Variants: Q8 S6 S7 S7C

[Paper-level Aggregated] PMCID: PMC7467277

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The text indicates that the genomic segment on chr8:208343-27992852 is associated with somatic copy number alterations (CNA), specifically deletions, which can contribute to tumorigenesis, suggesting an oncogenic role. Functional: The mention of somatic CNAs implies that the alterations may affect gene function, indicating a potential functional impact on the genes located within the specified genomic segment.

Gene→Variant (gene-first): NA:chr8:208343-27992852

Genes: NA

Variants: chr8:208343-27992852

[Paper-level Aggregated] PMCID: PMC7362646

Evidence Type(s): Oncogenic, Prognostic

Justification: Oncogenic: The IDH1 p.R132H mutation is mentioned as a significant alteration in adult gliomas, indicating its role in tumorigenesis. Prognostic: The presence of the IDH1 p.R132H mutation correlates with specific histological grades and patient age cohorts, suggesting it may have implications for patient outcomes.

Gene→Variant (gene-first): IDH1(3417):p.R132H

Genes: IDH1(3417)

Variants: p.R132H

[Paper-level Aggregated] PMCID: PMC7342819

Evidence Type(s): Oncogenic, Predisposing, Functional

Justification: Oncogenic: The presence of the KRAS p.G12V mutation is identified as a common driver mutation in pancreatic cancer, indicating its role in tumorigenesis. Predisposing: The germline mutation PALB2 c.3114-1G>A is noted as likely pathogenic and suggests a potential deficiency in DNA homologous recombination, which can predispose individuals to cancer. Functional: The identification of two deleterious PALB2 alterations, including both a germline and a somatic mutation, suggests functional implications related to DNA repair mechanisms.

Gene→Variant (gene-first): PALB2(79728):c.2514+1G>C PALB2(79728):c.3114-1G>A KRAS(3845):p.G12V

Genes: PALB2(79728) KRAS(3845)

Variants: c.2514+1G>C c.3114-1G>A p.G12V

[Paper-level Aggregated] PMCID: PMC7325368

Evidence Type(s): Oncogenic, Predictive, Prognostic

Justification: Oncogenic: The presence of B-RAFV600E and K-RAS mutations is associated with specific responses to treatment, indicating their role in tumorigenesis and cancer progression. Predictive: The study evaluates the efficacy of lifirafenib, a B-RAFV600E inhibitor, suggesting that the presence of this mutation can predict response to the treatment. Prognostic: The outcomes of patients with B-RAF and K-RAS mutations, including response rates and duration of response, provide prognostic information regarding their disease course and treatment efficacy.

Gene→Variant (gene-first): BRAF(673):B-RAFV600E KRAS(3845):G13D

Genes: BRAF(673) KRAS(3845)

Variants: B-RAFV600E G13D

[Paper-level Aggregated] PMCID: PMC7302243

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The presence of the T790M mutation in PC9/GR cells is associated with acquired resistance to EGFR-TKI, indicating its role in promoting cancer cell survival and proliferation despite treatment. Functional: The study demonstrates changes in protein expression and phosphorylation status in cells with the T790M mutation, suggesting that this variant affects cellular signaling pathways and functions related to tumor progression.

Gene→Variant (gene-first): EGFR(1956):T790M

Genes: EGFR(1956)

Variants: T790M

[Paper-level Aggregated] PMCID: PMC7294133

Evidence Type(s): Oncogenic, Functional, Prognostic

Justification: Oncogenic: The variant EPHB4-V871I is associated with increased proliferation, migration, and invasion properties in neuroblastoma cell lines, indicating its role in promoting tumorigenesis. Functional: The study demonstrates that EPHB4-V871I affects cellular functions such as proliferation and migration, and alters the expression of downstream target genes, confirming its functional impact in vitro. Prognostic: Higher EPHB4 expression, correlated with the EPHB4-V871I variant, is associated with advanced disease stages and poor overall survival in neuroblastoma patients.

Gene→Variant (gene-first): MYCN(4613):A417S EPHB4(2050):V871I ALK(238):F1174L

Genes: MYCN(4613) EPHB4(2050) ALK(238)

Variants: A417S V871I F1174L

[Paper-level Aggregated] PMCID: PMC7293710

Evidence Type(s): Oncogenic, Predictive

Justification: Oncogenic: The KRASG12V mutation is associated with increased sensitivity to metformin, indicating its role in promoting tumor growth and response to therapy in colorectal cancer cell lines. Predictive: The presence of the KRASG12V mutation predicts the response of CRC cells to metformin treatment, as evidenced by the differential effects observed in KRAS-mutated versus KRAS wild type cells.

Gene→Variant (gene-first): KRAS(3845):G12V

Genes: KRAS(3845)

Variants: G12V