This cohort study explores the association between clonal hematopoiesis of indeterminate potential and risk of incident pericarditis and myocarditis among participants in 2 large US biobanks.

Recent studies have reached opposing conclusions about whether clonal hematopoiesis (CH) is increased or decreased in patients with sickle cell disease (SCD). Given that CH is typically age-related, its presence in children with SCD could offer unique insights into early-life mutagenesis and disease-related stressors. We tested the primary and secondary hypotheses, that children with SCD would have a higher prevalence of CH when compared to age, sex, and race matched children without SCD; and children with hydroxyurea would have a higher CH prevalence than children not treated with hydroxyurea. To address this, we conducted a cross-sectional study in two independent cohorts of children, ages 0-18 years, with SCD (n=1,025 and n=1,293, respectively) and a 2,957-person matched comparison group. Using a highly sensitive, error-corrected sequencing assay capable of detecting CH at a variant allele frequency ≥ 0.5%, we found that children with SCD have a significantly higher prevalence of CH in relation to the comparison group (odds ratio (OR)=4.2, p=7.4x10-13). Additionally, CH was not associated with exposure to hydroxyurea therapy (OR=0.76, p=0.44).

OBJECTIVE:Clonal hematopoiesis (CH), defined by acquired driver mutations in hematopoietic stem cells, is associated with many inflammatory diseases of aging. We investigated whether CH and its subtypes, CH of indeterminate potential (CHIP) and mosaic chromosomal alteration (mCA), are associated with incident rheumatoid arthritis (RA) and whether complement modifies these associations. METHODS:CHIP was detected in NIH All of Us, Vanderbilt BioVU, and UK Biobank; mCA was detected in UK Biobank. A harmonized, high-specificity phenotyping algorithm was applied across biobanks to identify participants with seropositive and seronegative RA (SPRA and SNRA). Age-scale survival models assessed the effect of CH on risk of incident RA. Effect modification was tested with interaction models with genetically predicted complement protein levels. RESULTS:Among 612,989 participants, 30,840 had CHIP, 1,535 had incident SPRA, and 1,090 had incident SNRA. CHIP was associated with an increased risk of incident SPRA (pooled hazard ratio [HR] 1.26; confidence interval [CI] 1.03-1.52; P = 2.3 × 10-2), driven primarily by DNMT3A-mutated CHIP and late-onset RA (HR 1.45; CI 1.13-1.96; P = 3.6 × 10-3) but not SNRA. Autosomal mCA and mosaic loss of chromosome Y (mLOY) were associated with an increased risk of incident SPRA (HR 2.12 and 2.85; CI 1.18-3.8 and 1.57-5.19; P = 1.2 × 10-2 and 6.1 × 10-4) but not SNRA. Higher genetically predicted levels of C1r and C1s attenuated the CHIP-SPRA association. CONCLUSION:Age-related CH, including DNMT3A-CHIP, autosomal mCA, and mLOY, are risk factors for incident SPRA but not SNRA, supporting a genotype- and serostatus-specific link between somatic mutation and RA, with the classical complement pathway as a potential modifier.

Epidemiology studies underestimate the strength of the association between clonal hematopoiesis and disease due to false negatives from shallow, whole-genome sequencing versus deep targeted sequencing.

Abstract Background: Clonal hematopoiesis of indeterminate potential (CHIP) refers to clonal expansion of hematopoietic stem cells due to somatic mutations and is associated with heightened risk of myeloid neoplasms and cardiovascular diseases. Genotoxic therapies such as chemotherapy and radiation therapy are well-recognized contributors to CHIP in adult cancer population. However, CHIP prevalence, mutational patterns, and treatment associations in pediatric populations remain poorly characterized. Methods: We conducted a retrospective analysis of pediatric patients (age ≤ 18) diagnosed with cancer with blood samples collected after cancer therapy. CHIP was defined as the presence of a pathogenic somatic mutation in an accepted driver gene with variant allele frequency (VAF) ≥2%. CHIP prevalence was estimated overall and stratified by histology and therapeutic exposure. Logistic regression with Firth correction and exposure adjustment was used for multivariable analyses. TP53 variants with known Li-Fraumeni syndrome association and VAF >40% were considered germline mutations and excluded from analyses. Results: CHIP mutations were identified in 23 of 1,052 (2.2%) patients in this cohort. Mutations occurred most frequently in the TET2 (26%), DNMT3A (22%), and KRAS (13%) genes. CHIP prevalence was numerically higher among patients who received chemotherapy (3.3% vs. 1.4%, p=0.055). Multivariable analysis showed a modest female predominance (OR 0.45, p=0.04) and a trend toward higher CHIP risk with chemotherapy (OR 1.9, p=0.16). Among drug classes, antimetabolite therapy showed the highest CHIP prevalence (OR 3.46, p = 0.048), driven by methotrexate exposure (OR 21.5, p = 0.001). No correlations were found with age, histology, or radiation. Conclusion: We identified a low overall prevalence of CHIP in pediatric cancer patients and an association with antimetabolite therapy. Further studies are needed to define the long-term clinical implications of clonal hematopoiesis in pediatric cancer survivors.‬‬‬‬ Citation Format: Michael R. Kessler, Yash Pershad, Robert W. Corty, Eric T. Shinohara, Debra Friedman, Alexander G. Bick, Ben H. Park, Leo Y. Luo. Therapy-related clonal hematopoiesis in pediatric cancer survivors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7886.

Rationale:Sepsis is a life-threatening syndrome causing significant morbidity and mortality especially in the aging population. Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition of clonal expansion of hematopoietic stem cells harboring somatic mutations associated with increased incidence of chronic illness and all-cause mortality. Objective:Evaluate the association of pre-illness CHIP with mortality and morbidity in patients admitted to the ICU with sepsis. Methods:We performed a retrospective study using a de-identified electronic health record linked with a DNA biorepository. We identified adult patients with sepsis who had DNA collected prior to ICU admission. We tested the association between CHIP status, determined from whole-genome sequencing, and ICU mortality, organ support-free days, and long-term survival adjusting for age, sex, race and Sequential Organ Failure Assessment (SOFA) score on ICU admission. Measurements and Main Results:Pre-illness CHIP was associated with increased sepsis mortality (OR = 1.54, 95% CI 1.13 to 2.07, P = 0.005) and fewer days alive and free of organ support (-1.7 days, 95% CI -3.2 to -0.2, P = 0.028) after adjusting for age, sex, race, and SOFA score. In sepsis survivors, CHIP was also associated with increased long-term mortality after discharge (HR 1.40, 95% CI 1.01 to 1.93, P = 0.041). Conclusions:Pre-illness CHIP was independently associated with increased mortality and morbidity in critically-ill adults with sepsis. These findings suggest that CHIP is a risk factor for sepsis severity. Elucidating the mechanism underlying this association could uncover new therapeutic interventions for sepsis.

PURPOSE:Early intervention in patients with clonal hematopoiesis (CH) is an area of intense investigation with no currently approved agents. With recent mechanistic data on metformin as a possible therapeutic agent in CH and its availability in clinical practice, we sought to investigate the clonal dynamics of CH mutations in metformin users. EXPERIMENTAL DESIGN:We analyzed longitudinal targeted deep sequencing of 1,104 CH mutations in 863 metformin-treated type 2 diabetic participants in two longitudinal cohorts: the Women's Health Initiative (WHI) and BioVU, with blood collected at a median of 15.8 and 6.1 years apart, respectively. RESULTS:Metformin duration (per 6 months) was not significantly associated with the overall CH growth rate in WHI [β = -0.05%/year; 95% confidence interval (CI), -0.11 to 0.01; P = 0.08; n = 543] and in BioVU (β = -0.09%/year; 95% CI, -0.22 to 0.05; P = 0.20; n = 561). Inverse variance-weighted random-effects meta-analysis demonstrated a small, statistically significant association (β = -0.06%/year; 95% CI, -0.11 to -0.002; P = 0.04; n = 1,104) without significant heterogeneity (P = 0.60). These results were similar when only considering DNMT3A and DNMT3A-R882 clones. CONCLUSIONS:In our cohorts, the duration of metformin use among diabetic users was associated with a small reduction in CH growth rate (-0.06%/year), which is modest compared with typical DNMT3A clonal growth rates of 5% to 7% annually. Metformin's clinical utility for modulating clonal dynamics in real-world settings seems limited, and its clinical use for this indication requires further investigation in prospective studies.

Line plots showing change in VAF for all patients with detectable DNMT3A mutations, colored by clonal behavior.

Clonal hematopoiesis of indeterminate potential (CHIP) driven by somatic mutations in TET2 and DNMT3A is present in >10% of adults over 60 and confers substantial risk for hematologic malignancy and cardiovascular disease, yet the majority of patients with CHIP do not progress to disease. Analyzing 1,020,538 individuals across three biobanks (UK Biobank, All of Us, BioVU), we show that a discrete subset of enzymatically disruptive mutations - TET2 loss-off-unction variants and the DNMT3A R882 hotspot - account for the majority of clinical risk in these genes and exhibit the strongest clonal fitness advantage. Because DNMT3A and TET2 encode enzymes that modulate DNA methylation, we reasoned that peripheral blood methylation patterns should reflect the functional impact of individual mutations, enabling a direct readout of enzymatic dysfunction in CHIP patients. We developed and validated methylation-based activity scores for TET2 and DNMT3A as patient specific biomarkers that quantify enzymatic activity. These scores capture functional heterogeneity across mutation subtypes, predict disease risk comparably to clinical risk scores such as the Clonal Hematopoiesis Risk Score and the AHA PREVENT cardiovascular risk model. Integrating the activity score with the clinical models substantially improves prediction of incident cytopenia, myeloid neoplasm, and major adverse cardiovascular events. These findings establish that TET2 and DNMT3A CHIP pathogenicity is proportional to the degree of enzymatic disruption conferred by specific variants, and nominate methylation-based activity scores as a functional biomarker for individualized CHIP risk stratification and monitoring therapeutic response.

BACKGROUND:Clonal hematopoiesis of indeterminate potential (CHIP) is a common age-related condition that increases risk for cardiovascular disease. However, its relationship with stroke remains uncertain. METHODS:To resolve these conflicting findings, we analyzed genomic and clinical data from 800 160 participants with genetic sequencing and medical records across 3 large-scale cohorts: the Vanderbilt BioVU biobank (United States; enrollment 2007-2022), the National Institutes of Health All of Us Research Program (United States; enrollment 2018-2023), and the UK Biobank (United Kingdom; enrollment 2006-2010). The median follow-up time was 4.4 years (interquartile range, 1.8-10.2) in BioVU, 1.9 years (interquartile range, 0.4-3.9) in All of Us, and 12.4 years (interquartile range, 11.7-13.1) in UK Biobank. Stroke events were identified and classified as ischemic or hemorrhagic using International Classification of Diseases codes. Subgroup analyses were conducted by driver gene, clone size, sex, and menopausal status. Genetically predicted levels of 27 cytokines were assessed for modification of CHIP-associated stroke risk. RESULTS:CHIP was associated with increased risk of incident stroke in the meta-analysis (hazard ratio [HR], 1.20 [95% CI, 1.14-1.27]; P=1.92×10-10). This association was observed for ischemic (HR, 1.18) and hemorrhagic (HR, 1.25) stroke subtypes. Gene-specific analyses showed strong associations for JAK2 (HR, 2.52) and TET2 (HR, 1.23). DNMT3A demonstrated weak but significant associations (HR, 1.13). CHIP was associated with stroke risk in both sexes; however, among women, the association was evident in postmenopausal (HR, 1.49 [95% CI, 1.16-1.92]; P=1.91×10-3) but not in premenopausal participants (HR, 0.70 [95% CI, 0.36-1.43]; P=0.33). Among participants with CHIP, but not among participants without CHIP, genetically predicted levels of IL-1RAP (interleukin-1 receptor accessory protein) were predictive of risk for stroke, suggesting IL-1RAP as a modifier of the CHIP-associated risk for stroke. CONCLUSIONS:Our large-scale, multicohort study establishes CHIP as a determinant of incident stroke risk and IL (interleukin)-1-mediated inflammation as a targetable pathway to reduce this risk.

Somatic mutations that increase the fitness of hematopoietic stem cells (HSCs) drive their expansion in clonal hematopoiesis (CH) and predispose individuals to blood cancers. Population variation in the growth rate and potential of mutant clones suggests that genetic factors may confer resilience against CH. Here, we identified a noncoding regulatory variant, rs17834140-T, that protects against CH and myeloid malignancies by selectively down-regulating the RNA-binding protein MSI2 in HSCs. By modeling variant effects and mapping MSI2 binding targets, we uncovered an RNA network that maintains human HSCs and influences CH risk. Variant rs17834140-T was associated with slower CH expansion, and stem cell MSI2 levels modified ASXL1-mutant HSC clonal dominance. These findings leverage natural resilience to illuminate posttranscriptional regulation in human HSCs, suggesting that inhibition of MSI2 or its targets could be rational strategies for blood cancer prevention.

Importance:Cancer survivors have increased cardiovascular disease (CVD) risk partly due to the toxic effects of cancer therapy. Clonal hematopoiesis of indeterminate potential (CHIP), an age-associated blood disorder caused by somatic variants in blood stem cells, is more prevalent among individuals receiving cancer therapy and increases CVD risk independent of traditional risk factors. It is unknown whether CHIP amplifies therapy-related cardiovascular toxic effects in patients with cancer. Objective:To assess the association between CHIP and CVD risk, accounting for competing risks, among patients with primary solid tumors who received chemotherapy, radiotherapy, or immunotherapy. Design, Setting, and Participants:A cohort study was conducted using BioVU, Vanderbilt University Medical Center's biorepository linking electronic health records to whole-genome sequencing data from 250 038 participants from 2006 to 2025. In this cohort, participants had a primary solid tumor diagnosis, received chemotherapy, radiotherapy, and/or immunotherapy, and did not have hematologic malignant disease before treatment. Data were analyzed from June 2025 to November 2025. Exposures:CHIP variants detected via whole-genome sequencing, chemotherapy, radiotherapy, and immunotherapy. Main Outcomes and Measures:Time to first cardiovascular event, defined as heart failure, ischemic CVD, or arrhythmia following cancer treatment. Results:Among 8004 eligible participants (median [IQR] age, 61.9 [52.2-69.9] years; 4385 female individuals [54.8%]) with a primary solid tumor diagnosis, 7438 had no heart failure, 7392 no ischemic CVD, and 6002 no arrhythmia before cancer therapy. Overall, 549 (6.9%) had CHIP. In the propensity score-matched cohort, participants with CHIP had a significantly higher 10-year cumulative incidence of heart failure (20.3%; 95% CI, 16.0%-24.4% vs 14.5%; 95% CI, 13.5%-15.6%; P = .001) and ischemic CVD (25.3%; 95% CI, 20.5%-30.0% vs 18.5%; 95% CI, 17.3%-20.0%; P < .001) compared with those without CHIP. In adjusted Fine-Gray models, CHIP was associated with increased risk of heart failure (subdistribution hazard ratio [sHR], 1.26; 95% CI, 1.02-1.56; P = .03). In an exploratory 24-month landmark analysis, there was a statistically significant interaction between CHIP and intensive chemotherapy (≥7 cycles) on heart failure risk (sHR, 1.02; 95% CI, 1.00-1.04; P = .03). Conclusions and Relevance:In this cohort study, CHIP was associated with increased CVD risk in patients with solid tumors receiving cancer therapy. This finding suggests incorporating CHIP status may improve cardio-oncology treatment of cancer survivors.

AbstractPurpose: Early intervention in patients with clonal hematopoiesis (CH) is an area of intense investigation with no currently approved agents. With recent mechanistic data on metformin as a possible therapeutic agent in CH and its availability in clinical practice, we sought to investigate the clonal dynamics of CH mutations in metformin users. Experimental Design: We analyzed longitudinal targeted deep sequencing of 1,104 CH mutations in 863 metformin-treated type 2 diabetic participants in two longitudinal cohorts: the Women’s Health Initiative (WHI) and BioVU, with blood collected at a median of 15.8 and 6.1 years apart, respectively. Results: Metformin duration (per 6 months) was not significantly associated with the overall CH growth rate in WHI [β = −0.05%/year; 95% confidence interval (CI), −0.11 to 0.01; P = 0.08; n = 543] and in BioVU (β = −0.09%/year; 95% CI, −0.22 to 0.05; P = 0.20; n = 561). Inverse variance–weighted random-effects meta-analysis demonstrated a small, statistically significant association (β = −0.06%/year; 95% CI, −0.11 to −0.002; P = 0.04; n = 1,104) without significant heterogeneity (P = 0.60). These results were similar when only considering DNMT3A and DNMT3A-R882 clones. Conclusions: In our cohorts, the duration of metformin use among diabetic users was associated with a small reduction in CH growth rate (−0.06%/year), which is modest compared with typical DNMT3A clonal growth rates of 5% to 7% annually. Metformin’s clinical utility for modulating clonal dynamics in real-world settings seems limited, and its clinical use for this indication requires further investigation in prospective studies.

9549 Background: Clonal hematopoiesis (CH) arises from age-related somatic mutations in hematopoietic stem cells and has been linked to altered immune function and clinical outcomes in solid tumors. While recent studies in colorectal and lung cancers suggest TET2 -mutant CH may enhance immunotherapy responses, the impact of CH genotype on melanoma outcomes remains unclear and potentially context-dependent. Methods: We performed a retrospective cohort study of 361 patients with unresectable stage III/IV melanoma who underwent whole blood sequencing prior to anti-PD-1-based immunotherapy (2014-2024). CH was defined as somatic mutations in CH driver genes with variant allele fraction (VAF) > 2%. Progression-free survival (PFS) and overall survival (OS) were measured from ICI initiation; patients without events were censored at last follow-up. Kaplan-Meier curves and multivariable Cox models adjusted for age, sex, BRAF V600E status, stage, and prior therapy estimated hazard ratios (HRs) compared to patients without CH. Chi-squared analysis assessed CH prevalence among melanoma patients compared to a healthy control cohort (n = 12,346) matched for age and sex. Results: CH prevalence was significantly elevated in melanoma patients compared to age and sex-matched healthy controls (27.7% vs. 21.4% χ² = 7.94, p = 0.004). Among 361 patients, 32 (8.9%) harbored TET2 -driven CH, 48 (13.3%) had DNMT3A -CH, and 20 (5.5%) had other CH mutations. TET2 -CH was associated with significantly worse OS compared to patients without CH (HR = 1.79, p = 0.014) and a trend toward inferior PFS (HR = 1.42, p = 0.119). In contrast, neither DNMT3A -CH (N = 48) nor other CH genotypes demonstrated significant associations with clinical outcomes ( DNMT3A -CH: OS HR = 1.38, p = 0.11; PFS HR = 1.21, p = 0.32), establishing genotype-specific effects. Conclusions: In this cohort of patients with unresectable Stage III/IV melanoma receiving ICI therapy, TET2 -CH was associated with inferior survival outcomes, while no significant survival differences were found among patients with DNMT3A -CH or other CH genotypes. Incorporating CH genotyping into pre-treatment risk stratification may identify high-risk melanoma patients who could benefit from alternative or intensified therapeutic strategies. Mechanistic studies are warranted to elucidate the biological basis for these genotype-specific effects and explore therapeutic interventions targeting CH-driven immune dysfunction. Multivariable PFS and OS hazard ratios by clonal hematopoiesis genotype in ICI-treated melanoma patients. CH Group Number (N) PFS HR (95% CI) PFS p-value OS HR (95% CI) OS p-value No CH 261 1.00 (reference) - 1.00 (reference) - CH 100 1.21 (0.92-1.60) 0.178 1.48 (1.10-1.99) 0.010 TET2- CH 32 1.42 (0.91-2.19) 0.119 1.79 (1.12-2.84) 0.014 Non- TET2 CH 68 1.13 (0.82-1.56) 0.445 1.36 (0.97-1.92) 0.079 DNMT3A -CH 48 1.21 (0.83-1.74) 0.319 1.38 (0.93-2.03) 0.108

Small particulate matter air pollution (PM2.5) is a recognized driver of non-small cell lung cancer (NSCLC), including in non-smoking individuals. Inhaled PM2.5 recruits pro-inflammatory macrophages to the air-lung interface, which promotes malignant lung epithelial cell growth and progression to overt cancer. Smoking is recognized to potentiate this process, though no factors potentiating risk among non-smoking individuals have been identified. We sought to determine whether clonal hematopoiesis of indeterminate potential (CHIP), a common age-related condition characterized by hyperinflammatory macrophages, synergizes with PM2.5 to promote NSCLC in non-smoking individuals using genetic, environmental, and phenotypic data from over 650,000 people in the UK Biobank and All of Us cohorts. In meta-analysis, CHIP was associated with a greater risk of NSCLC in never-smoking participants (hazard ratio (HR)=1.76[1.07-2.89]). This risk is exacerbated in the setting of above-median PM2.5 levels (HR = 2.51[1.55 to 4.05]; p-interaction = 0.02). The CHIP x PM2.5 interaction also associated with elevated markers of systemic inflammation (CRP, IL-6, and IL-1β). Together, these results suggest CHIP and PM2.5 form a novel somatic gene × environment interaction promoting inflammation and NSCLC tumorigenesis in non-smoking individuals.

Abstract Clonal hematopoiesis of indeterminate potential (CHIP) represents the age-related expansion of hematopoietic stem cells with preleukemic mutations. However, its association with all-cause and cause-specific mortality has not been well characterized in older adults. We aimed to evaluate whether CHIP is associated with all-cause and cause-specific mortality in a population of older women in the United States. Our study included 6,704 participants in the Women’s Health Initiative Long Life Study (WHI-LLS) without hematologic malignancy. The co-primary exposures were any CHIP (variant allele frequency [VAF] ≥ 2%) and large CHIP (VAF ≥ 10%), and the primary outcome was all-cause mortality. Multivariable-adjusted Cox proportional hazards models tested the associations of CHIP and CHIP subtypes with all-cause and cause-specific mortality. Any CHIP and large CHIP were independently associated with all-cause mortality, with multivariable-adjusted hazard ratios (aHRs) of 1.12 (95% confidence interval [CI] 1.04-1.21; P = 0.003) and 1.28 (95% CI 1.15-1.43; P < 0.001), respectively. In gene-specific analyses, non- DNMT3A CHIP was associated with all-cause mortality (aHR: 1.22 [95% CI: 1.12-1.34], P < 0.001), while DNMT3A CHIP was not (aHR: 1.07 [95% CI: 0.98-1.18], P = 0.13). Furthermore, large CHIP was associated with cardiovascular (aHR: 1.29 [95% CI: 1.08-1.55], P = 0.006), cancer (aHR: 1.49 [95% CI: 1.11-2.02], P = 0.009), and neurologic (aHR: 1.40 [95% CI: 1.07-1.84], P = 0.02) death. In this cohort of older women, CHIP, particularly large clones and non- DNMT3A CHIP, was associated with all-cause and cause-specific mortality. These findings suggest that clonal size and subtype may differentially influence mortality risk.

e18584 Background: SH2B3 is an adaptor protein that downregulates JAK-STAT signaling by binding JAK2. Loss-of-function mutations in SH2B3 have been implicated in myeloproliferative neoplasms (MPN), myelodysplastic syndromes (MDS), and MDS/MPN. However, SH2B3 variants in myeloid neoplasms are classified as variants of uncertain significance (VUS), and their clinical relevance is poorly understood. This analysis aims to characterize the clinico-genomic features of patients with SH2B3 variants. Methods: We performed a single-center, retrospective study of patients with SH2B3 variants identified on myeloid targeted DNA-sequencing. Available clinical and genomic data were collected from electronic medical records. Results: Our cohort included 57 patients (62% female) with median age of 64 years. SH2B3 variants (all VUS) were largely SNVs (88%), with median VAF of 48.4% (4.2-79.1%). The most common variants were p.Glu395Lys (n=6), p.Asp485_Trp492del (n=5), and p.Ser213Arg (n=5), concentrated in PH and SH2 domains. Common pathogenic co-mutations (present in 41% of cases) included JAK2 (n=8), TET2 (n=7), and DNMT3A (n=5). Hematologic abnormalities were common: thrombocytosis (32%), anemia (30%), leukocytosis (28%), thrombocytopenia (25%), and basophilia (23%). Overall, 34 patients (60%) had a cytopenic (anemia, neutropenia, and/or thrombocytopenia) phenotype, and 20 (35%) had a cytoses (leukocytosis, polycythemia, and/or neutrophilia) phenotype. Bone marrow evaluation (n=44) showed hypocellularity (25%), megakaryocytic atypia (32%), and hyperplasia (30%); 16% harbored abnormal karyotypes. Notably, in patients without pathogenic co-mutations (n=33), characteristic hematologic abnormalities (thrombocytosis 30%, anemia 21%, and thrombocytopenia 21%) and bone marrow morphologic changes (megakaryocytic atypia 30%) were common. Only 6% of this subset had a myeloid malignancy diagnosis, suggesting underestimation of these neoplasms. Conclusions: SH2B3 variants are associated with frequent hematologic abnormalities and characteristic bone marrow morphologic changes, even in the absence of pathogenic co-mutations. Hence, detection of the SH2B3 variant, even if a VUS, should raise suspicion of MDS or MPN in appropriate context. External validation of our findings is being performed using NIH’s All of Us database, and updated results will be presented at the meeting. Clinico-genomic characteristics of patients with SH2B3 variants. All (N=57) SH2B3 Variants With Pathogenic Co-mutation (N=24) SH2B3 Variants Without Pathogenic Co-mutation (N=33) Age, median (range) 64 (20-87) 67 (33-87) 62 (20-82) Hematology Thrombocytosis, n (%) 18 (32%) 8 (33%) 10 (30%) Anemia, n (%) 17 (30%) 10 (42%) 7 (21%) Leukocytosis, n (%) 16 (28%) 9 (38%) 7 (21%) Thrombocytopenia, n (%) 14 (25%) 7 (29%) 7 (21%) Bone Marrow (n=44) Megakaryocytic atypia, n (%) 15 (34%) 8 (38%) 7 (30%) Dysplasia, n (%) 6 (14%) 4 (19%) 2 (9%)