NM_012433.2:c.1873C>T

SF3B1 · NP_036565.2:p.(Arg625Cys) · NM_012433.2

GRCh37: chr2:198267484 G>A · GRCh38: chr2:197402760 G>A

Gene: SF3B1 Transcript: NM_012433.2

Final call

VUS

PM1 moderate PM2 supporting PP3 supporting

Variant details

Gene

SF3B1

Transcript

NM_012433.2

Protein

NP_036565.2:p.(Arg625Cys)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

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.

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.

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.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	Although gene-level review indicates that loss of function can be relevant for SF3B1, this variant is a missense substitution and does not fall within the generic PVS1 null-variant categories of nonsense, frameshift, or canonical +/-1,2 splice-site change.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	Not assessed	No evidence was identified showing that this amino acid change has an established pathogenic counterpart caused by a different nucleotide substitution.	clinvar
PS2	Not assessed	No de novo occurrence with confirmed maternity and paternity was identified.	clinvar
PS3	Not assessed	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.	PMID:23861464 PMID:24434863 PMID:26565915 PMID:33031100
PS4	Not met	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.	clinvar PMID:23313955 PMID:23861464 PMID:24434863 PMID:26565915
PM1	Met	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.	PMID:23313955 PMID:23861464 PMID:24434863 PMID:26565915 PMID:33031100 hotspots
PM2	Met	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 gnomad_v4
PM3	N/A	No recessive disease context or trans observation with another pathogenic variant was identified for this variant.
PM4	N/A	This variant is a missense substitution and does not change protein length.
PM5	Not assessed	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.	clinvar PMID:23313955
PM6	Not assessed	No assumed de novo occurrence without full parental confirmation was identified.	clinvar
PP1	Not assessed	No segregation data were identified.	clinvar
PP2	Not assessed	Available evidence does not establish a gene-specific missense constraint framework suitable for PP2 application in this review.	final_classification_framework
PP3	Met	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 bayesdel spliceai
PP4	Not assessed	No patient-specific phenotype or family history was provided that would support a highly specific clinical presentation for PP4.
PP5	N/A	A ClinVar record is present, but no submission classification or review status could be confirmed from the available data, so PP5 cannot be applied.	clinvar
BA1	Not met	Population frequency is well below the BA1 threshold of 1.0%. The highest observed overall frequency was 1.85894e-06 (0.00019%) in gnomAD v4.1.	gnomad_v2 gnomad_v4
BS1	Not met	Population frequency is below the BS1 threshold of 0.3%. The highest observed subgroup frequency was 8.81228e-06 (0.00088%) in gnomAD v2.1 European non-Finnish and 2.54257e-06 (0.00025%) in gnomAD v4.1 European non-Finnish.	gnomad_v2 gnomad_v4
BS2	Not assessed	No evidence was identified showing this variant in healthy adult individuals in a manner sufficient for BS2.	gnomad_v2 gnomad_v4
BS3	Not met	Available functional evidence does not support normal protein function. Published studies instead show that SF3B1 hotspot mutations are associated with abnormal splicing, and no well-established assay demonstrating a normal result for p.Arg625Cys was identified.	PMID:23861464 PMID:24434863 PMID:26565915 PMID:33031100
BS4	Not assessed	No lack-of-segregation data were identified.	clinvar
BP1	N/A	BP1 does not apply because this is a missense variant in a gene where disease-relevant missense variation is well documented.	PMID:23313955 PMID:23861464 PMID:24434863 PMID:26565915
BP2	Not assessed	No phase information with another pathogenic variant was identified.
BP3	N/A	This variant is not an in-frame deletion or insertion in a repetitive region.
BP4	Not met	Available computational evidence does not support a benign interpretation. REVEL is 0.823 and BayesDel is 0.321224, both favoring a damaging missense effect, although SpliceAI predicts no significant splice impact with a max delta score of 0.03.	revel bayesdel spliceai
BP5	Not assessed	No alternate molecular diagnosis was identified that would explain a phenotype independently of this variant.
BP6	N/A	A ClinVar record is present, but no supporting benign classification details or review status were available for BP6 application.	clinvar
BP7	N/A	BP7 does not apply because this is a missense variant rather than a synonymous or deep intronic change.

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