About SF3B1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
SF3B1 c.2098A>G, p.(Lys700Glu)
Classification
Likely pathogenic
Variant description:
No variant summary was recorded for this case.
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.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
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Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 4
Benign evidence criteria: 0
Pathogenic criteria applied · 4
PS3Moderate
PS3 · moderate
SF3B1 K700E has been directly tested in multiple independent publications demonstrating unequivocal gain-of-function effects on RNA splicing. K700E expression causes aberrant 3' splice site selection and cryptic branchpoint usage (PMID:21909114, PMID:26565915), generates a conserved alternative splicing signature across cancer types (PMID:24434863, PMID:25424858), and promotes tumorigenesis through MYC stabilization via PPP2R5A mis-splicing, confirmed in isogenic Nalm-6 cell lines and conditional Sf3b1 K700E/+ knock-in mice (PMID:32188705). Functional effects are well-established; however, data derive from somatic cancer models and the relevance to germline disease is not fully resolved.
PM1Moderate
PM1 · moderate
Residue K700 lies within the HEAT repeat domain (H4-H8) of SF3B1, a structurally and functionally critical region essential for branchpoint recognition and 3' splice site selection during pre-mRNA splicing. This residue is a statistically significant mutational hotspot in cancer (cancerhotspots.org) and is the most frequently mutated codon in SF3B1 across hematologic malignancies and solid tumors (PMID:21909114, PMID:32188705).
PM2Supporting
PM2 · supporting
This variant is present at very low frequency in population databases. gnomAD v2.1 allele frequency is 8.31×10⁻⁵ (0.0083%, 23/276,636 alleles, 0 homozygotes); gnomAD v4.1 allele frequency is 4.49×10⁻⁵ (0.0045%, 72/1,604,090 alleles, 0 homozygotes). Both are below the 0.1% PM2 threshold for a rare variant absent from population controls.
PP3Supporting
PP3 · supporting
REVEL score of 0.619 exceeds the commonly used 0.5 threshold, supporting a deleterious effect. BayesDel score of 0.234 is below most pathogenicity thresholds. SpliceAI max delta of 0.03 predicts no splicing impact. In silico evidence is mixed but REVEL provides supporting-level evidence for pathogenicity.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Likely pathogenic
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PS3 moderate, PM1 moderate, PM2 supporting, PP3 supporting; combination = 2 moderate + 2 supporting, which maps to Likely Pathogenic.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
72 / 1,604,090 alleles
gnomAD v4.1: 72 / 1,604,090 alleles. Recorded AF 4.48853e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 8.31417e-05; MAF= 0.00831%, 23/276636 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.000297147; MAF= 0.02971%, 3/10096 alleles, homozygotes = 0); grpmax FAF= 6.863e-05.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.00027165054873410846, 5/18406 alleles, homozygotes = 0).
SpliceAI score
0.030 maximum delta
Recorded SpliceAI maximum delta score: 0.030. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
5 reported laboratory submissions
2 Uncertain significance · 2 Likely pathogenic · 1 Pathogenic. ClinVar API review status: criteria provided, conflicting classifications.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; curated oncogenicity label: Likely Oncogenic.
COSMIC
Cancer Hotspots
Somatic evidence
811 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV59205318, n = 811 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
26 criteria with recorded statuses: 4 met · 21 not met · 1 not assessed · 0 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
SF3B1 c.2098A>G (p.Lys700Glu) is a missense variant located in the HEAT repeat domain (H4-H8), a critical functional region essential for 3' splice site recognition during pre-mRNA splicing.
This variant is the most recurrent SF3B1 hotspot across hematologic malignancies and solid tumors, with 811 somatic occurrences in COSMIC and statistical significance at cancerhotspots.org.
Multiple independent functional studies demonstrate that K700E causes aberrant 3' splice site selection, cryptic branchpoint usage, and a conserved alternative splicing signature, confirmed in isogenic Nalm-6 cell lines and conditional Sf3b1 K700E/+ knock-in mice.
Mechanistically, K700E promotes MYC protein stabilization through aberrant splicing and nonsense-mediated decay of PPP2R5A, a regulatory subunit of the PP2A phosphatase complex, leading to oncogenic transformation.
The variant is present at very low frequency in population databases (gnomAD v2.1: 0.0083%, 23/276,636 alleles; gnomAD v4.1: 0.0045%, 72/1,604,090 alleles), meeting the PM2 threshold for rarity.
ClinVar reports conflicting classifications: Uncertain significance (2 laboratories), Likely pathogenic (2 laboratories), and Pathogenic (1 laboratory, somatic), with an aggregate 1-star review status (criteria provided, single submitter).
In silico predictions are mixed: REVEL (0.619) supports a deleterious effect, while BayesDel (0.234) is ambiguous and SpliceAI (0.03) predicts no splicing impact.
This variant meets PS3 (moderate), PM1 (moderate), PM2 (supporting), and PP3 (supporting). No benign criteria are met. The functional data strength is tempered by its derivation from somatic cancer models; correlation with germline disease phenotype requires clinical review.
No criteria match.
Met · 4
PS3 ModerateSF3B1 K700E has been directly tested in multiple independent publications demonstrating unequivocal gain-of-function effects on RNA splicing. K700E expression causes aberrant 3' splice site selection and cryptic branchpoint usage (PMID:21909114, PMID:26565915), generates a conserved alternative splicing signature across cancer types (PMID:24434863, PMID:25424858), and promotes tumorigenesis through MYC stabilization via PPP2R5A mis-splicing, confirmed in isogenic Nalm-6 cell lines and conditional Sf3b1 K700E/+ knock-in mice (PMID:32188705). Functional effects are well-established; however, data derive from somatic cancer models and the relevance to germline disease is not fully resolved. Details ▾Hide ▴
Evidence considered
- K700E identified as recurrent hotspot in MDS
- gain-of-function splicing defects (PMID:21909114)
- K700E-associated splicing signature conserved across MDS
- CLL
- and uveal melanoma (PMID:24434863)
- K700E causes differential exon usage in breast cancer
- SF3B1 mutant cells selectively sensitive to spliceostatin A (PMID:25424858)
- K700E promotes MYC stabilization via PPP2R5A aberrant splicing
- verified in isogenic Nalm-6 cells and Sf3b1 K700E/+ mice (PMID:32188705)
Still missing
- Functional data is derived from somatic/cancer models
- direct germline functional studies of K700E are lacking
- Relevance of somatic splicing defects to germline disease phenotype requires clinical correlation
Sources
PM1 ModerateResidue K700 lies within the HEAT repeat domain (H4-H8) of SF3B1, a structurally and functionally critical region essential for branchpoint recognition and 3' splice site selection during pre-mRNA splicing. This residue is a statistically significant mutational hotspot in cancer (cancerhotspots.org) and is the most frequently mutated codon in SF3B1 across hematologic malignancies and solid tumors (PMID:21909114, PMID:32188705). Details ▾Hide ▴
Evidence considered
- K700 is the predominant SF3B1 hotspot across cancers (PMID:21909114: K700E=44 cases
- PMID:32188705)
- Located in HEAT H4-H8 domain critical for U2 snRNP-branchpoint interaction
- Statistically significant hotspot residue by cancerhotspots.org
- COSMIC n=811 somatic occurrences at this residue
Sources
PM2 SupportingThis variant is present at very low frequency in population databases. gnomAD v2.1 allele frequency is 8.31×10⁻⁵ (0.0083%, 23/276,636 alleles, 0 homozygotes); gnomAD v4.1 allele frequency is 4.49×10⁻⁵ (0.0045%, 72/1,604,090 alleles, 0 homozygotes). Both are below the 0.1% PM2 threshold for a rare variant absent from population controls. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: AF=8.31×10⁻⁵
- 23/276
- 636 alleles
- 0 homozygotes
- gnomAD v4.1: AF=4.49×10⁻⁵
- 72/1
- 604
- 090 alleles
- grpmax FAF v4.1: 4.04×10⁻⁵
Sources
PP3 SupportingREVEL score of 0.619 exceeds the commonly used 0.5 threshold, supporting a deleterious effect. BayesDel score of 0.234 is below most pathogenicity thresholds. SpliceAI max delta of 0.03 predicts no splicing impact. In silico evidence is mixed but REVEL provides supporting-level evidence for pathogenicity. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.619 (above 0.5 threshold)
- BayesDel score: 0.234 (below 0.27 threshold)
- SpliceAI max delta: 0.03 (no predicted splicing impact)
Still missing
- HCI prior not available for SF3B1
Sources
Not met · 21 · evaluated, threshold not reached
PVS1 NM_012433.3:c.2098A>G is a missense variant (p.Lys700Glu) and does not fall into any generic PVS1 null-variant category (nonsense, frameshift, or canonical ±1,2 splice site). The ClinGen SVI PVS1 framework (PMC6185798) does not apply to this variant class. Details ▾Hide ▴
PS1 No evidence that a different nucleotide change at codon 700 resulting in the same amino acid substitution (p.Lys700Glu) has been previously established as pathogenic in a germline context. Details ▾Hide ▴
Still missing
- No same-amino-acid pathogenic variant identified at this codon via a different nucleotide change
PS2 No de novo occurrence data available for this variant with confirmed maternity and paternity. While de novo SF3B1 germline missense variants have been reported in neurodevelopmental disorders (PMID:41577671), these are distinct variants from K700E and do not provide de novo evidence for this specific variant. Details ▾Hide ▴
Still missing
- No de novo testing performed for this variant
PS4 No case-control study demonstrating statistically significant enrichment of this variant in affected individuals versus controls in a germline context. The variant is frequent in somatic cancers (COSMIC n=811) but this does not satisfy PS4 for germline interpretation. Details ▾Hide ▴
Still missing
- No germline case-control data available
PM5 No qualifying comparator variant at the same residue (K700) with a different amino acid change classified as pathogenic was identified. Automated ClinVar PM5 candidate harvesting returned no results. Details ▾Hide ▴
No further detail was recorded.
PM6 No confirmed de novo occurrence of this variant with maternity and paternity testing has been reported. Details ▾Hide ▴
Still missing
- No de novo testing data available
PP1 No co-segregation data with disease in multiple affected family members is available for this variant. Details ▾Hide ▴
Still missing
- No segregation analysis available
PP4 No patient-specific phenotypic information was available for review. PP4 requires a phenotype highly specific for a disease with a single genetic etiology; this cannot be evaluated without clinical data. Details ▾Hide ▴
Still missing
- No patient phenotype or family history available for review
PP5 ClinVar aggregate classification is Uncertain significance (review status: criteria provided, single submitter; 1-star). Submissions are split: 2 VUS, 2 Likely pathogenic, 1 Pathogenic (somatic). No expert panel review is present. The 3-star expert panel requirement for PP5 at supporting is not met. Details ▾Hide ▴
Evidence considered
- ClinVar classification: Uncertain significance
- 1-star review status
- Submissions: VUS (2 labs)
- Likely pathogenic (2 labs)
- Pathogenic (1 lab
- somatic)
- No expert panel submission
Sources
BA1 gnomAD v2.1 allele frequency of 0.0083% is well below the 1% BA1 threshold for a benign stand-alone classification. Details ▾Hide ▴
BS1 gnomAD v2.1 allele frequency of 0.0083% is below the 0.3% BS1 threshold for a benign strong classification. The variant is rare in population databases. Details ▾Hide ▴
BS2 No evidence of observation in healthy adult individuals for a disorder with full penetrance expected at an early age. BS2 also requires the variant to be observed in trans with a pathogenic variant or in a homozygous state in an unaffected individual, none of which has been documented. Details ▾Hide ▴
No further detail was recorded.
BS3 Functional studies uniformly demonstrate deleterious gain-of-function effects: K700E causes aberrant 3' splice site selection, cryptic branchpoint usage, MYC stabilization, and oncogenic transformation (PMID:21909114, PMID:25424858, PMID:32188705). No functional study supports a benign or neutral effect. BS3 is clearly contradicted by the available evidence. Details ▾Hide ▴
Evidence considered
- K700E causes aberrant splicing in multiple independent studies
- Isogenic cell lines and mouse models confirm gain-of-function effects
- No study demonstrates neutral or benign functional impact
Sources
BS4 No evidence of lack of segregation in affected family members. No segregation data is available for this variant. Details ▾Hide ▴
Still missing
- No segregation data available
BP1 This is a missense variant (p.Lys700Glu). BP1 applies only when a missense variant is found in a gene where primarily truncating variants cause disease. SF3B1 germline disease is associated with both truncating and missense variants (PMID:41577671), and K700E is a missense change in a known functional hotspot. Details ▾Hide ▴
Evidence considered
- SF3B1 disease spectrum includes missense variants (PMID:41577671)
BP2 No evidence of observation in trans with a known pathogenic variant for a fully penetrant dominant disorder, nor in cis with a pathogenic variant in a recessive disorder. Details ▾Hide ▴
No further detail was recorded.
BP4 In silico evidence is mixed and does not meet the requirement for multiple lines of computational evidence suggesting no impact. REVEL score of 0.619 supports a deleterious effect. BayesDel (0.234) is ambiguous. SpliceAI (0.03) predicts no splice impact. The overall computational evidence does not point uniformly toward benignity. Details ▾Hide ▴
Evidence considered
- REVEL 0.619: predicts deleterious
- BayesDel 0.234: ambiguous
- SpliceAI 0.03: predicts no splicing impact
Sources
BP5 SF3B1 is a gene in which variants have been reported as pathogenic. BP5 requires the variant to be found in a case with an alternate molecular basis for disease. This information is not available for the present case. Details ▾Hide ▴
Still missing
- No alternate molecular diagnosis identified
BP6 ClinVar aggregate classification is Uncertain significance (1-star). No reputable source classifies this variant as Benign or Likely benign. BP6 requires a 3-star expert panel classification as benign; this is not met. Details ▾Hide ▴
Evidence considered
- ClinVar classification: VUS (1-star)
- no benign classification from any submitter
Sources
BP7 This is a missense variant (c.2098A>G, p.Lys700Glu), not a synonymous or intronic variant. BP7 is only applicable to synonymous variants with no predicted splicing impact. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 applies only to synonymous variants
PS5 No evidence that a different missense change at codon 700 (e.g., K700R, K700N) has been established as pathogenic in a germline context. While other K700 variants exist somatically, no ClinVar germline pathogenic classification for a distinct K700 substitution was identified. Details ▾Hide ▴
Still missing
- No ClinVar pathogenic germline classification for an alternative K700 missense change
Not assessed · 1 · no assessment recorded
PP2 Constraint metrics (e.g., gnomAD missense Z-score, LOEUF) were not directly reviewed for SF3B1. While SF3B1 is a known disease gene and de novo missense variants cause neurodevelopmental disorders (PMID:41577671), formal constraint analysis is needed to determine whether the gene has a low rate of benign missense variation meeting PP2 thresholds. Details ▾Hide ▴
Still missing
- gnomAD constraint metrics not reviewed
- missense Z-score and LOEUF needed to adjudicate
Identifiers
- Gene
- SF3B1
- Transcript
- NM_012433.3
- Coding (HGVS c.)
- NM_012433.3:c.2098A>G
- Protein (HGVS p.)
- NP_036565.2:p.(Lys700Glu)
- GRCh38
- chr2:197402110 T>C
- GRCh37
- chr2:198266834 T>C
- ClinVar
- 376004
- COSMIC
- COSV59205318
Gene diagram
Every interpreted variant in SF3B1, mapped onto the exon structure of NM_012433.3. Select a row to find it on the plot.
SF3B1NM_012433.3
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in SF3B1
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
72 / 1,604,090 alleles
AF 4.49e-05 · 0 homozygotes · FAF 4.04e-05
gnomAD v2.1
23 / 276,636 alleles
AF 8.31e-05 · 0 homozygotes · FAF 6.86e-05
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 4.5e-05 · 72 / 1,604,090 alleles · 0 hom · FAF 4e-05
| Ashkenazi Jewish5 / 29,376 | 0.00017 |
| European (non-Finnish)60 / 1,174,390 | 5.1e-05 |
| Remaining individuals2 / 62,054 | 3.2e-05 |
| European (Finnish)2 / 63,946 | 3.1e-05 |
| East Asian1 / 44,700 | 2.2e-05 |
| Admixed American1 / 58,006 | 1.7e-05 |
| South Asian1 / 90,212 | 1.1e-05 |
0 alternate alleles recorded in 3 other groups: Amish, Middle Eastern, African/African American.
gnomAD v2.1
AF 8.3e-05 · 23 / 276,636 alleles · 0 hom · FAF 6.9e-05
| Ashkenazi Jewish3 / 10,096 | 0.0003 |
| Remaining individuals1 / 7,082 | 0.00014 |
| European (non-Finnish)14 / 127,392 | 0.00011 |
| South Asian2 / 29,602 | 6.8e-05 |
| African/African American1 / 24,828 | 4e-05 |
| European (Finnish)1 / 25,020 | 4e-05 |
| Admixed American1 / 33,010 | 3e-05 |
0 alternate alleles recorded in 1 other group: East Asian.
gnomAD-Canada
AF not recorded · ? / ? alleles
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 4.48853e-05; MAF= 0.00449%, 72/1604090 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.000170207; MAF= 0.01702%, 5/29376 alleles, homozygotes = 0); grpmax FAF= 4.038e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 8.31417e-05; MAF= 0.00831%, 23/276636 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.000297147; MAF= 0.02971%, 3/10096 alleles, homozygotes = 0); grpmax FAF= 6.863e-05.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.00027165054873410846, 5/18406 alleles, homozygotes = 0).
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.619
- BayesDel
- 0.234
How the predictions were used
PP3 SupportingREVEL score of 0.619 exceeds the commonly used 0.5 threshold, supporting a deleterious effect. BayesDel score of 0.234 is below most pathogenicity thresholds. SpliceAI max delta of 0.03 predicts no splicing impact. In silico evidence is mixed but REVEL provides supporting-level evidence for pathogenicity. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.619 (above 0.5 threshold)
- BayesDel score: 0.234 (below 0.27 threshold)
- SpliceAI max delta: 0.03 (no predicted splicing impact)
Still missing
- HCI prior not available for SF3B1
Sources
BP4 In silico evidence is mixed and does not meet the requirement for multiple lines of computational evidence suggesting no impact. REVEL score of 0.619 supports a deleterious effect. BayesDel (0.234) is ambiguous. SpliceAI (0.03) predicts no splice impact. The overall computational evidence does not point uniformly toward benignity. Details ▾Hide ▴
Evidence considered
- REVEL 0.619: predicts deleterious
- BayesDel 0.234: ambiguous
- SpliceAI 0.03: predicts no splicing impact
Sources
BP7 This is a missense variant (c.2098A>G, p.Lys700Glu), not a synonymous or intronic variant. BP7 is only applicable to synonymous variants with no predicted splicing impact. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 applies only to synonymous variants
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.619. BayesDel score = 0.233816.
9 paper records listed. 5 cited in the classification.
Cited in the classification
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PMID 21909114 ↗Frequent pathway mutations of splicing machinery in myelodysplasia.SF3B1 K700E identified as the predominant recurrent hotspot mutation in myelodysplastic syndromes through whole-exome sequencing. K700E accounted for 44 of 79 SF3B1 mutations. Mutations were mutually exclusive with other splicing factor mutations and strongly associated with ring sideroblasts. Functional studies demonstrated that mutant spliceosome components induce abnormal RNA splicing and compromised hematopoiesis.→ PS3 → PM1 Names this variant
Source detail
SF3B1 mutations predominantly involved K700 and, to a lesser extent, K666, H662 and E622, which are also conserved across species.
Location Figure 2; Results paragraphs 2-4
Context Whole-exome sequencing of 29 MDS specimens; large cohort validation in 582 myeloid neoplasms; HeLa cell expression of mutant U2AF35 with GSEA
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PMID 23160465 ↗Biologic and clinical significance of somatic mutations of SF3B1 in myeloid and lymphoid neoplasms.Comprehensive review of SF3B1 mutations in myeloid and lymphoid neoplasms. K700E is described as accounting for more than 50% of all observed SF3B1 variants. Mutations cluster in exons 12-16 within HEAT domains. SF3B1 mutations are founding genetic lesions in MDS with ring sideroblasts and are associated with favorable prognosis in MDS but poor prognosis in CLL.→ PS3 Names this variant
Source detail
The K700E mutation accounted for more than 50% of the variants observed, and additional codons (666, 662, 622, and 625) were found to be hot spots for mutation.
Location Paragraph 'SF3B1 mutations in myeloid neoplasms'
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PMID 24434863 ↗A common alternative splicing signature is associated with SF3B1 mutations in malignancies from different cell lineages.Identified a common alternative splicing signature associated with SF3B1 mutations across malignancies from different cell lineages (CLL, MDS, uveal melanoma). K700E was the most frequent mutation in CLL (6/8) and MDS (14/24) samples. The splicing signature was independent of the specific mutated HEAT repeat and tumor type, arguing for a direct consequence of the mutation.→ PS3 Names this variant
Source detail
K700E (6), K666T (1) and G742D (1) ... K700E (14), H622Q (4), D781G (2), R625L/H/D/C (4)
Location Results paragraphs 2-4
Context RT-QPCR splicing analysis of UQCC, CRNDE, ANKHD1, GUSBP1, ABCC5 in 161 tumor samples (CLL, MDS, UM)
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PMID 25424858 ↗SF3B1 mutations constitute a novel therapeutic target in breast cancer.Systematic analysis of SF3B1 mutations in breast cancer. K700E accounted for 74% (17/23) of SF3B1 mutant tumors and was enriched in ER-positive disease and special histological types (papillary, mucinous). K700E mutant tumors displayed a conserved differential splicing signature. SF3B1 K700E mutant cell lines (Panc 05.04) showed selective sensitivity to the SF3b complex inhibitor spliceostatin A, demonstrating therapeutic dependency on the mutant allele.→ PS3 Names this variant
Source detail
K700E mutations were identified in 6% (1/18), 16% (3/19), and 0% (0/28) of mucinous, papillary, and micropapillary carcinomas, respectively.
Location Results sections 'SF3B1 K700E mutations are associated with differential splicing' and 'SF3B1 mutant cells are sensitive to SF3b inhibition'
Context RNA-seq of papillary breast carcinomas; spliceostatin A treatment of Panc 05.04 (K700E) vs wild-type pancreatic and endometrial cell lines; siRNA silencing of differentially spliced targets
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PMID 32188705 ↗Mutations in the RNA Splicing Factor SF3B1 Promote Tumorigenesis through MYC Stabilization.Liu Z et al. · 2020 JunPan-cancer analysis of SF3B1 hotspot mutations across 98 tumors and 12 isogenic cell lines. K700E was the most common mutation in CLL, MDS, AML, and BRCA. Regulatory network analysis identified MYC as the top master regulator activated specifically in K700E-mutant cancers. Mechanistically, K700E causes aberrant splicing and NMD of PPP2R5A, reducing PP2A-mediated dephosphorylation of c-MYC at S62, stabilizing MYC protein. Conditional Sf3b1 K700E/+ knock-in mice crossed with Eμ-Myc mice developed B-cell leukemia/lymphoma. K700E-mutant cells were preferentially sensitive to pharmacologic PP2A activation with FTY-720.→ PS3 → PM1 Names this variant
Source detail
The most frequent hotspot, K700E, was the most common mutation in CLL, MDS, acute myeloid leukemia (AML), and BRCA
Location Results sections throughout; Figures 2-7
Context Isogenic Nalm-6 K700E/+ knock-in cells; conditional Sf3b1 K700E/+ knock-in mice; CLL patient RNA-seq; FTY-720 PP2A activator treatment; cycloheximide chase for MYC half-life; BCL2-BAK co-immunoprecipitation
Other recorded publications
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PMID 23335386 ↗Spliceosome mutations involving SRSF2, SF3B1, and U2AF35 in chronic myelomonocytic leukemia: prevalence, clinical correlates, and prognostic relevance.Study of spliceosome mutations in 226 CMML patients. SF3B1 mutations were found in 6% of cases, primarily K700E. Mutations in SRSF2, SF3B1, and U2AF35 were mutually exclusive. SF3B1-mutated cases had significantly higher ring sideroblast percentages. No prognostic relevance was found for SF3B1 mutations in CMML.Names this variant
Quoted passage
mutational frequencies were 40% for SRSF2 (all affecting P95), 6% for SF3B1 (primarily K700E) and 9% for U2AF35
Abstract; Results section
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PMID 25741868 ↗Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.Richards S et al. · 2015ACMG/AMP standards and guidelines for the interpretation of sequence variants. Provides the generic classification framework used in this assessment but does not discuss the SF3B1 K700E variant.Does not name this variant
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PMID 35101336 ↗Standards for the classification of pathogenicity of somatic variants in cancer (oncogenicity): Joint recommendations of Clinical Genome Resource (ClinGen), Cancer Genomics Consortium (CGC), and Variant Interpretation for Cancer Consortium (VICC).Horak P et al. · 2022ClinGen/CGC/VICC joint recommendations for somatic variant oncogenicity classification. Discusses standards for classifying somatic variants in cancer but does not specifically address the SF3B1 K700E variant.Does not name this variant
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PMID 23619274 ↗American College of Medical Genetics and Genomics technical standards and guidelines: microarray analysis for chromosome abnormalities in neoplastic disorders.Cooley LD et al. · 2013No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
72 / 1,604,090 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.030
Open source ↗
ClinVar
2 Uncertain significance · 2 Likely pathogenic · 1 Pathogenic
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/376004/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/2-198266834-T-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr2-197402110-T-C?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/2-197402110-T-C
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_012433.3%3Ac.2098…
- OncoKB ↗www.oncokb.org/gene/SF3B1/K700E
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=126501088
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 4.48853e-05; MAF= 0.00449%, 72/1604090 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.000170207; MAF= 0.01702%, 5/29376 alleles, homozygotes = 0); grpmax FAF= 4.038e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 8.31417e-05; MAF= 0.00831%, 23/276636 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.000297147; MAF= 0.02971%, 3/10096 alleles, homozygotes = 0); grpmax FAF= 6.863e-05.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.00027165054873410846, 5/18406 alleles, homozygotes = 0).
ClinVar
This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories) and as Likely pathogenic (2 clinical laboratories) and as Pathogenic (1 clinical laboratory). (ClinVarID = 376004)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.619. BayesDel score = 0.233816.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; curated oncogenicity label: Likely Oncogenic.
Somatic
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV59205318, n = 811 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.