The SF3B1 c.1873C>T (p.Arg625Cys; p.R625C) variant has been observed repeatedly in somatic cancers and is recorded in ClinVar, while published studies identify codon 625 as a recurrently mutated SF3B1 hotspot.1 This variant is rare in population databases, with 1/251128 alleles in gnomAD v2.1 (AF 3.98203e-06; 0.00040%) and 3/1613820 alleles in gnomAD v4.1 (AF 1.85894e-06; 0.00019%), both below the 0.1% PM2 threshold.2 In published functional studies, SF3B1 hotspot-mutant tumors and model systems showed altered alternative splicing and abnormal 3' splice-site selection, supporting functional importance of the codon 625 region, although exact p.Arg625Cys assay-level evidence remains limited.3 Computational evidence supports a deleterious missense effect, with REVEL 0.823 and BayesDel 0.321224, while SpliceAI predicts no significant splice disruption with a maximum delta score of 0.03.4
Final classification
VUS
PM1PM2PP3
SF3B1
c.1873C>T
p.Arg625Cys
This variant
The SF3B1 c.1873C>T (p.Arg625Cys; p.R625C) variant has been observed repeatedly in somatic cancers and is recorded in ClinVar, while published studies identify codon 625 as a recurrently mutated SF3B1 hotspot.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM1 moderate, PM2 supporting, PP3 supporting; combination = 1 moderate + 2 supporting, which maps to VUS.
Classification rationale
PM1PM2PP3
VUS
SF3B1 c.1873C>T
PM1 + PM2 + PP3
→
VUS
LYFE Sciences is an AI system, and it can make mistakes. Criteria
may be applied incorrectly, sources may be misread, and a confident-looking
classification can still be wrong. Double-check every criterion and
its underlying evidence before relying on any call.
Gene diagram
· NM_012433.2 · variants mapped to exon structure
SF3B1
NM_012433.2
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 17 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
PM1
moderate
review
Pathogenic
This missense variant affects Arg625, a recurrent SF3B1 hotspot reported across multiple studies, and published functional work on SF3B1 hotspot mutations shows abnormal 3' splice-site selection, supporting that this residue lies in a mutational hotspot and functionally important region.
Codon 625 recurrence reported in uveal melanoma and other malignanciesSF3B1 hotspot mutations induce aberrant splicing
PM2
supporting
review
Pathogenic
Population frequency is below the PM2 threshold of 0.1%. In gnomAD v2.1 this variant was seen in 1/251128 alleles (AF 3.98203e-06; 0.00040%), and in gnomAD v4.1 in 3/1613820 alleles (AF 1.85894e-06; 0.00019%), with no homozygotes observed.
gnomAD v2.1 AF 3.98203e-06gnomAD v4.1 AF 1.85894e-06
PP3
supporting
review
Pathogenic
Multiple computational findings support a deleterious missense effect. REVEL is 0.823 and BayesDel is 0.321224, both consistent with a damaging protein effect, while SpliceAI shows no meaningful splice disruption (max delta score 0.03), which does not offset the missense prediction signal.
REVEL 0.823BayesDel 0.321224SpliceAI max delta 0.03
Assessed · not applied
· 5 not met · 12 not assessed
Pathogenic
PS1
No evidence was identified showing that this amino acid change has an established pathogenic counterpart caused by a different nucleotide substitution.
PS2
No de novo occurrence with confirmed maternity and paternity was identified.
PS3
Published studies show that SF3B1 hotspot mutations can alter RNA splicing and downstream signaling, but the available evidence does not clearly establish a well-validated assay result for this exact p.Arg625Cys variant that is sufficient for PS3.
PS4
This variant has been reported in somatic cancers and is present in ClinVar, but no germline case-control dataset or statistically increased prevalence in affected individuals versus controls was identified, so PS4 is not met.
PM5
Other changes at codon 625 have been reported in cancer literature, but a clearly established pathogenic missense variant at the same residue suitable for germline PM5 application was not confirmed from the available evidence.
PM6
No assumed de novo occurrence without full parental confirmation was identified.
PP1
No segregation data were identified.
PP2
Available evidence does not establish a gene-specific missense constraint framework suitable for PP2 application in this review.
PP4
No patient-specific phenotype or family history was provided that would support a highly specific clinical presentation for PP4.
Benign
BA1
Population frequency is well below the BA1 threshold of 1.0%.
BS1
Population frequency is below the BS1 threshold of 0.3%.
BS2
No evidence was identified showing this variant in healthy adult individuals in a manner sufficient for BS2.
BS3
Available functional evidence does not support normal protein function.
BS4
No lack-of-segregation data were identified.
BP2
No phase information with another pathogenic variant was identified.
BP4
Available computational evidence does not support a benign interpretation.
BP5
No alternate molecular diagnosis was identified that would explain a phenotype independently of this variant.
N/A · 8
PVS1 · PM3 · PM4 · PP5 · BP1 · BP3 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 1.85894e-06; MAF= 0.00019%, 3/1613820 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.54257e-06; MAF= 0.00025%, 3/1179908 alleles, homozygotes = 0); grpmax FAF= 6.8e-07.
v2.1
This variant is present in gnomAD v2.1 (AF= 3.98203e-06; MAF= 0.00040%, 1/251128 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.81228e-06; MAF= 0.00088%, 1/113478 alleles, homozygotes = 0).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00019%
· 3 / 1,613,820
0 hom · FAF 6.8e-05%
0 hom · FAF 6.8e-05%
European (non-Finnish) 3 / 1,179,908 |
0.00025% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.0004%
· 1 / 251,128
0 hom
0 hom
European (non-Finnish) 1 / 113,478 |
0.00088% |
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
ClinVar
This variant has been reported in ClinVar but submission details could not be extracted.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.823. BayesDel score = 0.321224.
Functional
Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; curated oncogenicity label: Likely Oncogenic.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV59205859, n = 105 times).
Hotspots
This variant lies in a statistically significant hotspot.
Literature · how each cited paper was used
5papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.
Recurrent mutations at codon 625 of the splicing factor SF3B1 in uveal melanoma.
Found
Structured finding pending for this record — see source link.
Applied to
→PM1
moderate
SF3B1 mutations are associated with alternative splicing in uveal melanoma.
Found
Structured finding pending for this record — see source link.
Applied to
→PM1
moderate
A common alternative splicing signature is associated with SF3B1 mutations in ma
Found
Structured finding pending for this record — see source link.
Applied to
→PM1
moderate
Cancer-Associated SF3B1 Hotspot Mutations Induce Cryptic 3' Splice Site Selectio
Found
Structured finding pending for this record — see source link.
Applied to
→PM1
moderate
Mutant SF3B1 promotes AKT- and NF-κB-driven mammary tumorigenesis.
Found
Structured finding pending for this record — see source link.
Applied to
→PM1
moderate
Sources & reference links