The CSF3R NM_000760.4:c.1853C>T (NP_000751.1:p.(Thr618Ile)) missense variant has previously been reported in somatic cancers (COSMIC; COSV58963463, n = 118 times). Experimental evidence: Variant-specific mouse transplantation and colony assays show cytokine-independent growth, granulocytic expansion, and lethal myeloproliferative disease. Based on available guidelines, this variant is considered to be Likely Pathogenic.
Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.
Likely pathogenic.A likely pathogenic classification under the recorded framework.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.CSF3R encodes a cell-surface receptor for granulocyte colony-stimulating factor, which promotes the production, maturation, and function of neutrophils and other granulocytes. Loss of CSF3R function can cause severe congenital neutropenia, also known as Kostmann syndrome. CSF3R can act as an oncogene in blood cancers, particularly myeloid disorders, and its abnormal activation may also contribute to some solid tumors.
The recorded framework is Generic ACMG/AMP 2015 with ClinGen SVI recommendations. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
The applied criteria and their strengths are shown as assessed under the stated framework.
Met, moderate: variant-specific mouse transplantation and colony assays show cytokine-independent growth, granulocytic expansion, and lethal myeloproliferative disease.
Met: CSF3R T618I occurred in 10/12 CNL cases versus 0/170 comparison controls, yielding continuity-corrected OR 1,432.2 (95% CI 64.5–31,782.9), above 5 with CI excluding 1.
Met at supporting: the variant is absent from gnomAD v2.1, v4.1, and non-cancer subsets, meeting the <=0.0001 PM2 threshold.
Met, supporting: missense REVEL score 0.143 is below the <=0.29 BP4 supporting threshold.
Likely Pathogenic: PS4 strong plus PS3 moderate satisfy the generic ACMG/AMP 2015 rule, with PM2 supporting; BP4 alone does not create conflicting evidence.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1 allele counts were not recorded for this variant.
Absent from gnomAD v2.1.
Not available in gnomAD-Canada v1.0.
Recorded REVEL score: 0.143. Refer to the recorded PP3/BP4 rationale for interpretation.
2 Pathogenic · 2 Likely pathogenic. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Gain-of-function; curated oncogenicity label: Oncogenic.
This variant has previously been reported in somatic cancers (COSMIC; COSV58963463, n = 118 times).
This variant does not lie in a statistically significant hotspot.
ACMG/AMP criteria under Generic ACMG/AMP 2015 with ClinGen SVI recommendations, with the data and sources behind each one.
28 criteria with recorded statuses: 4 met · 7 not met · 12 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
The queried variant is CSF3R NM_000760.4:c.1853C>T, NP_000751.1:p.(Thr618Ile).
No VCEP covers CSF3R; generic ACMG/AMP 2015 definitions govern.
Among the requested criteria, PM1 and BP1 are not met; PS1, PM5, and PP2 remain not assessed because their required comparator or gene-level evidence was not established.
No criterion among PS2, PM6, PP1, and BS4 can be applied from the available case-specific segregation or parental-testing evidence.
The ClinVar submission signal for segregation is too nonspecific to establish PP1 and does not provide evidence for BS4.
PS4 is met from the directly verified Pardanani et al. case-control data: 10/12 WHO-defined CNL cases versus 0/170 CMML/PMF comparison controls, with a continuity-corrected OR of 1,432.2 and approximate 95% CI 64.5–31,782.9.
PP4 and BP5 are not assessed because patient-level phenotype/family-history and alternate-molecular-basis evidence are unavailable; experimental mouse co-mutation data do not substitute for a human BP5 case.
PP5 and BP6 are not met because ClinVar has no expert-panel classification for this exact variant; its laboratory submissions are not eligible under the specified generic rules.
Allelic evidence does not support PM3 because no recessive CSF3R disorder is established and no trans testing is documented.
BP2 remains not assessed because no pathogenic partner variant or cis/trans phase observation is documented.
No criteria match.
PS3 is met at moderate strength. The exact CSF3R c.1853C>T (p.Thr618Ile; T618I) variant was tested in a murine bone-marrow transplantation model, where expression in hematopoietic cells was sufficient to produce a lethal myeloproliferative disorder with granulocytic overproduction and tissue infiltration (PMID:24081659). An independent study of the same variant used murine bone-marrow colony-forming and serial-replating assays, cytokine-free culture, molecular analyses, and transplantation models; T618I produced cytokine-independent colonies and promoted granulocytic proliferation, while combination with CEBPA mutation markedly intensified the phenotype and produced lethal leukemia (PMID:31784538). These variant-specific in vivo and cellular functional results support an activating, damaging effect. Moderate rather than strong strength is assigned because the available extracts do not document clinical diagnostic-laboratory validation, full assay-control details, or independent reproducibility sufficient for the highest functional strength.
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
PS4 is met. Pardanani et al. directly studied the queried CSF3R T618I variant (also called T595I) and found it in 10 of 12 WHO-defined CNL cases (83%), while it was absent from 9 WHO-defined aCML cases, 6 MG-associated CNL cases, 17 unconfirmed CNL cases, 10 unconfirmed aCML cases, and 170 CMML/PMF controls. Using the explicitly reported 10/12 affected-case count and the 0/170 CMML/PMF comparison-control count, the zero control cell was handled with a Haldane–Anscombe 0.5 continuity correction: OR = (10.5 x 170.5)/(2.5 x 0.5) = 1,432.2; approximate 95% CI = 64.5–31,782.9. Thus OR >5.0 and the 95% CI excludes 1.0. The paper is a case-control comparison even though it does not print an odds ratio; the odds ratio and confidence interval were computed from its counts.
The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. ... Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0.
PM2 is met at supporting strength. The exact CSF3R c.1853C>T (p.Thr618Ile) variant is absent from gnomAD v2.1 and gnomAD v4.1, as well as the non-cancer gnomAD v2.1 and v3.1 searches. This satisfies the generic PM2 supporting threshold of <=0.0001; absence is compatible with PM2 for the recessive CSF3R-deficiency condition listed in ClinVar, while no frequency-based claim is made for the variant's somatic neoplasm associations.
Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
This is a missense variant, NM_000760.4:c.1853C>T (p.Thr618Ile) in exon 14, so the generic PP3/BP4 missense path requires REVEL only; SpliceAI and BayesDel are not used for this criterion. The REVEL score is 0.143, which is at or below the supplied generic BP4 supporting threshold of <= 0.29 (ClinGen SVI calibration, Pejaver et al. 2022, PMID:36413997), so BP4 is met at supporting strength.
BP4: Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc) ... BP4 (supporting): <= 0.29 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
The case has no VCEP materials or authoritative CSF3R domain table. The Cancer Hotspots query for CSF3R T618 returned no statistically significant hotspot, while COSMIC recurrence of the exact variant in 118 somatic cancers does not by itself establish a generic ACMG hotspot or critical functional domain. No well-established critical domain without benign variation was documented, so PM1 is not met.
Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.
This is a missense variant, NM_000760.4:c.1853C>T (p.Thr618Ile) in exon 14, so the generic PP3/BP4 missense path requires REVEL only; SpliceAI and BayesDel are not used for this criterion. The REVEL score is 0.143, below the supplied generic PP3 supporting threshold of >= 0.644 (ClinGen SVI calibration, Pejaver et al. 2022, PMID:36413997), so PP3 is not met.
PP3: Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). ... PP3 (supporting): >= 0.644 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
PP5 is not met. ClinVar Variation ID 208339 contains Pathogenic and Likely pathogenic laboratory submissions, but the record has zero expert-panel submissions and is labeled 'criteria provided, multiple submitters, no conflicts,' not an expert-panel classification. Under the specified generic rule, ordinary laboratory submissions, aggregate labels, and non-expert assertions cannot trigger PP5.
Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.
BA1 is not met. The queried CSF3R c.1853C>T (p.Thr618Ile) variant is absent from gnomAD v2.1, gnomAD v4.1, gnomAD v2.1 non-cancer, and gnomAD v3.1 non-cancer; therefore no allele frequency approaches the generic BA1 threshold of >=0.05 (5%). There is no population-frequency basis for a stand-alone benign call, and the variant has a documented pathogenic/likely pathogenic ClinVar consensus, although that consensus is not used as the basis for this criterion.
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
BS1 is not met. The variant is absent from gnomAD v2.1, gnomAD v4.1, gnomAD v2.1 non-cancer, and gnomAD v3.1 non-cancer, so no filtering allele frequency is available and the observed frequency cannot exceed the generic >=0.01 threshold. Because there is no elevated population frequency, a maximum-credible-allele-frequency calculation is not needed for this criterion.
Allele frequency is greater than expected for the disorder.
The extracted CSF3R literature reports truncation mutations in severe congenital neutropenia but also identifies activating missense mutations affecting the extracellular domain in hereditary neutrophilia and chronic neutrophilic leukemia; T618I is a recurrent activating missense variant. Therefore, CSF3R disease is not characterized as primarily truncating for the relevant disease spectrum, so BP1 is not met.
Missense variant in a gene for which primarily truncating variants are known to cause disease.
BP6 is not met. ClinVar Variation ID 208339 contains no exact-variant benign or likely benign expert-panel classification; instead, it contains Pathogenic and Likely pathogenic laboratory submissions with no expert-panel submissions. Ordinary laboratory submissions, aggregate labels, and non-expert assertions cannot trigger BP6 under the specified generic rule.
Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.
The variant is CSF3R p.Thr618Ile (c.1853C>T), and the literature establishes this exact substitution. However, the available evidence does not identify a previously established pathogenic alternate nucleotide change producing the same Thr618Ile amino-acid change. The required same-amino-acid comparator is therefore not available for assessment.
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. ... Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.
The available record identifies the variant as germline in two ClinVar submissions, but provides no proband-level documentation of the disease phenotype, no family-history assessment, and no confirmed maternity and paternity testing. Therefore, the evidence is insufficient to assess PS2.
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
The evidence establishes CSF3R p.Thr618Ile but does not identify a different missense substitution at residue Thr618 that has been determined to be pathogenic. The available same-variant literature therefore does not provide a qualifying PM5 comparator.
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. ... Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.
The available record does not document an assumed de novo occurrence in a proband, and it does not report whether maternity or paternity was unconfirmed. Germline submission origin alone does not establish PM6.
Assumed de novo, but without confirmation of paternity and maternity.
One ClinVar submitter's evidence signal states only that the variant was observed to segregate with disease in related individuals; it gives no affected-relative count, genotypes, phenotypes, meioses, or segregation details. This is insufficient to establish PP1 or justify increased strength.
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease. ... Note: May be used as stronger evidence with increasing segregation data.
CSF3R disease-associated truncating and activating missense variants are documented, supporting a missense disease mechanism, but no validated gene-level measure demonstrating a low rate of benign missense variation was provided. Absence of this variant from gnomAD cannot establish that gene-level requirement, so PP2 is not assessed.
Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.
PP4 cannot be assessed from the available evidence because the case materials do not provide the patient's phenotype or family history, and the reviewed literature concerns cohort-level disease associations rather than this patient's highly specific clinical presentation. No patient-specific phenotype is available to evaluate against a single genetic etiology.
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
BS2 cannot be assessed from the available evidence. The case materials do not document the queried variant in a healthy adult as homozygous for a recessive disorder, heterozygous for a dominant disorder, or hemizygous for an X-linked disorder, and they do not establish the relevant inheritance model, age-related penetrance, or adult health status for an observation that could satisfy BS2. Population absence is not evidence for a healthy-adult observation.
Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.
No variant-specific functional study in the reviewed evidence demonstrates that CSF3R p.Thr618Ile has no damaging effect on protein function or splicing. The available functional studies instead report activating phenotypes, so they cannot establish BS3.
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
The available evidence contains no affected-family-member genotype and phenotype data demonstrating that the variant fails to segregate with disease. The vague positive segregation statement in one ClinVar submission does not establish non-segregation or address phenocopies and multiple pathogenic variants.
Lack of segregation in affected members of a family. ... Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals.
BP2 cannot be assessed from the available evidence. The governing rule requires either observation in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observation in cis with a pathogenic variant in any inheritance pattern. No affected-proband report, parental or offspring testing, haplotype/phase result, or documented pathogenic variant in cis or trans is provided for CSF3R c.1853C>T (p.Thr618Ile).
Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.
BP5 cannot be assessed because no patient-level evidence shows that this variant was found in a case with an alternate molecular basis for disease. The reviewed CSF3R T618I literature includes experimental co-occurrence with CEBPA mutations in mouse models, but that is not a human case demonstrating an alternate molecular basis and does not establish BP5 for this case.
Variant found in a case with an alternate molecular basis for disease.
PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_000760.4:c.1853C>T in CSF3R is a missense substitution predicted to produce NP_000751.1:p.(Thr618Ile). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PVS1 for CSF3R, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_null_variant_class
PM3 is not applicable because the available case evidence does not establish a recessive CSF3R disorder. The variant is reported as a germline activating CSF3R T618I mutation in hereditary neutrophilia and as a recurrent somatic driver in myeloid neoplasms; neither context is a recessive disorder requiring PM3. No parental or offspring phase testing, affected-proband trans observation, or pathogenic variant in trans is documented.
For recessive disorders, detected in trans with a pathogenic variant ... Note: This requires testing of parents (or offspring) to determine phase.
PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_000760.4:c.1853C>T in CSF3R is a missense substitution predicted to produce NP_000751.1:p.(Thr618Ile). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PM4 for CSF3R, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel
BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_000760.4:c.1853C>T in CSF3R is a missense substitution predicted to produce NP_000751.1:p.(Thr618Ile). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP3 for CSF3R, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_repeat_region_indel
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_000760.4:c.1853C>T in CSF3R is a missense substitution predicted to produce NP_000751.1:p.(Thr618Ile). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for CSF3R, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
Every interpreted variant in CSF3R, mapped onto the exon structure of NM_000760.4. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
Absent from gnomAD v4.1.
Absent from gnomAD v2.1.
Not available in gnomAD-Canada v1.0.
This is a missense variant, NM_000760.4:c.1853C>T (p.Thr618Ile) in exon 14, so the generic PP3/BP4 missense path requires REVEL only; SpliceAI and BayesDel are not used for this criterion. The REVEL score is 0.143, which is at or below the supplied generic BP4 supporting threshold of <= 0.29 (ClinGen SVI calibration, Pejaver et al. 2022, PMID:36413997), so BP4 is met at supporting strength.
BP4: Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc) ... BP4 (supporting): <= 0.29 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
This is a missense variant, NM_000760.4:c.1853C>T (p.Thr618Ile) in exon 14, so the generic PP3/BP4 missense path requires REVEL only; SpliceAI and BayesDel are not used for this criterion. The REVEL score is 0.143, below the supplied generic PP3 supporting threshold of >= 0.644 (ClinGen SVI calibration, Pejaver et al. 2022, PMID:36413997), so PP3 is not met.
PP3: Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). ... PP3 (supporting): >= 0.644 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_000760.4:c.1853C>T in CSF3R is a missense substitution predicted to produce NP_000751.1:p.(Thr618Ile). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for CSF3R, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.143. BayesDel score = 0.0404795.
9 paper records listed. 3 cited in the classification.
The most frequent CSF3R mutation we encountered was CSF3RT618I (also annotated as CSF3R T595I); we did not have access to germline DNA to confirm the somatic nature of the other genetic variations including CSF3RM696T and I598I.
Location Results, ‘CSF3R and SETBP1 mutation results’; Introduction and Discussion
Context CSF3R exons 14–17 were PCR-amplified and analyzed by capillary Sanger sequencing in clinically suspected CNL or aCML cases; the cohort included 12 WHO-defined CNL patients.
Here we demonstrate that the most prevalent, activating mutation, CSF3R T618I, is sufficient to drive a lethal myeloproliferative disorder in a murine bone marrow transplantation model.
Location Abstract
Context Murine bone-marrow transplantation model using hematopoietic cells expressing CSF3R T618I; disease phenotype assessed by granulocyte production and tissue infiltration.
As previously reported, CSF3RT618I produced a modest number of colonies in isolation9. The addition of CEBPAV314VW, but not CEBPAF82fs, dramatically augmented CSF3RT618I-driven colony production and produced indefinite replating (Fig. 1c).
Location Results, “Cooperativity Between CSF3RT618I and CEBPA Mutations,” paragraph 1; Fig. 1 and related Results sections
Context Murine bone-marrow retroviral-transduction colony-forming and serial-replating assays; cytokine-free liquid culture morphology; RNA-seq and gene-expression analyses; murine bone-marrow transplantation leukemia models; flow cytometry, histology, and enhancer ChIP-seq in HoxB8-ER cells.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
Absent from gnomAD v4.1.
Absent from gnomAD v2.1.
Not available in gnomAD-Canada v1.0.
This variant has been reported in ClinVar as Pathogenic (2 clinical laboratories) and as Likely pathogenic (2 clinical laboratories). (ClinVarID = 208339)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.143. BayesDel score = 0.0404795.
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Gain-of-function; curated oncogenicity label: Oncogenic.
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV58963463, n = 118 times).
This variant does not lie in a statistically significant hotspot.