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
SF3B1
Final classification
VUS
SF3B1 c.1873C>T · p.Arg625Cys
SF3B1
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
Gene diagram
· NM_012433.2 · variants mapped to exon structure
SF3B1
NM_012433.2
Fetching transcript structure from UCSC…
Applied criteria · 3 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
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.
PMID PMID:23313955
Found
Structured finding pending for this record — see source link.
Applied to
→PM1 supports · met
PMID PMID:23861464
Found
Structured finding pending for this record — see source link.
Applied to
→PM1 supports · met
PMID PMID:24434863
Found
Structured finding pending for this record — see source link.
Applied to
→PM1 supports · met
PMID PMID:26565915
Found
Structured finding pending for this record — see source link.
Applied to
→PM1 supports · met
PMID PMID:33031100
Found
Structured finding pending for this record — see source link.
Applied to
→PM1 supports · met
Sources & reference links