Variant classification summary

NM_006758.3:c.101C>T

U2AF1 · NP_006749.1:p.(Ser34Phe) · NM_006758.3

GRCh37: chr21:44524456 G>A · GRCh38: chr21:43104346 G>A

Gene: U2AF1 Transcript: NM_006758.3

Final call

Likely Pathogenic

PS3 strong PM2 supporting PP3 supporting

Variant details

Gene

U2AF1

Transcript

NM_006758.3

Protein

NP_006749.1:p.(Ser34Phe)

gnomAD AF

0.0 (v4.1)

ClinVar

Oncogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Likely Pathogenic: PS3 strong—independent cell, biochemical, minigene, and mouse studies show abnormal splicing and related cellular dysfunction.

2

Likely Pathogenic: PM2 supporting—the variant is absent from gnomAD v4.1 and has AF 3.56e-6 in gnomAD v2.1.

3

Likely Pathogenic: PP3 supporting—REVEL is 0.7, meeting the adjudicated supporting threshold.

Final determination: Under the generic ACMG/AMP 2015 fallback, one strong pathogenic criterion plus two supporting pathogenic criteria leads to Likely Pathogenic.

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	Not applicable: PVS1 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not met	Not met: recurrent p.Ser34Phe reports are somatic, but no previously established pathogenic variant with the same amino-acid change was identified.	PMID:22158538 clinvar
PS2	Not assessed	Not assessed: no documented affected proband with confirmed maternity and paternity, and no documented absence of family history.
PS3	Met	Met, strong: independent cell, biochemical, minigene, and mouse studies consistently show U2AF1 S34F causes abnormal splicing and related cellular dysfunction.	PMID:22158538 PMID:25267526 PMID:25311244 PMID:25965570 PMID:30054334 PMID:30842218
PS4	Not assessed	Not assessed: 11/150 affected individuals were reported, but no matched unaffected-control count supports the required OR >5.0 with a 95% CI excluding 1.0.	PMID:22158538 gnomad_v2 gnomad_v4
PM1	Not assessed	Not assessed: residue 34 lies in the first zinc finger, but domain-wide absence of benign variation and an allowed hotspot route are not established.	PMID:25267526 gnomad_v2 gnomad_v4 hotspots
PM2	Met	Met at supporting strength: AF is 3.56e-6 in gnomAD v2.1 and 0 in v4.1, both below the <=0.0001 PM2 threshold.	gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no recessive disease context or parent/offspring phase data establish U2AF1 p.S34F in trans with a pathogenic variant.	PMID:22158538 PMID:25267526 PMID:25965570 PMID:30054334 PMID:30842218
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not met	Not met: p.Ser34Tyr is an alternate missense at residue 34, but its pathogenic status is not established under ACMG/AMP.	PMID:22158538 PMID:25965570
PM6	Not assessed	Not assessed: no documented affected proband with an assumed de novo occurrence or available parental testing results.
PP1	Not assessed	Not assessed: no affected relatives or informative meioses are documented to demonstrate co-segregation with disease.
PP2	Not assessed	Not assessed: recurrent U2AF1 missense mutations are documented, but no validated gene-wide benign-missense rate and mechanism assessment is available.	PMID:22158538 PMID:25267526
PP3	Met	Met at supporting strength: missense REVEL score 0.7 meets the >=0.644 PP3 threshold.	revel
PP4	Not met	Not met: the reported myelodysplastic syndrome phenotype is not highly specific for a disease with a single genetic etiology.	PMID:22158538
PP5	Not met	Not met: ClinVar shows single-submitter Oncogenic and no exact-variant expert-panel Pathogenic or Likely pathogenic classification is available.	clinvar oncokb
BA1	Not assessed	Not assessed: grpmax FAF is unavailable, while observed AF is 3.56e-6 in gnomAD v2.1 and 0 in v4.1 versus the 5% BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Not assessed	Not assessed: grpmax FAF and disorder-specific maximum credible frequency are unavailable; observed AF is 3.56e-6 versus the 1% generic BS1 default.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: gnomAD shows 0 homozygotes, but no documented healthy adult with qualifying zygosity, age, phenotype, and early-onset full-penetrance disease context exists.	gnomad_v2 gnomad_v4
BS3	Not met	Not met: six variant-specific studies report abnormal splicing or cellular dysfunction, with no validated normal-function assay for U2AF1 S34F.	PMID:22158538 PMID:25267526 PMID:25311244 PMID:25965570 PMID:30054334 PMID:30842218
BS4	Not assessed	Not assessed: no affected relatives with documented variant-negative testing are available to demonstrate lack of segregation.
BP1	Not met	Not met: the documented U2AF1 disease-associated pattern is recurrent missense substitution at S34 and Q157, not primarily truncating variation.	PMID:22158538 PMID:25267526 PMID:25311244
BP2	Not assessed	Not assessed: no affected-proband or family phase data show U2AF1 p.S34F in trans or cis with a pathogenic variant.	PMID:22158538 PMID:25267526 PMID:25965570 PMID:30054334 PMID:30842218
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: missense REVEL score 0.7 exceeds the <=0.29 BP4 supporting threshold.	revel
BP5	Not assessed	Not assessed: the available case reports do not document an alternate molecular diagnosis explaining disease in a patient carrying U2AF1 p.Ser34Phe.	PMID:22158538
BP6	Not met	Not met: no exact-variant ClinVar expert-panel Benign or Likely benign classification is available; the record is single-submitter Oncogenic.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a missense variant.	generic_acmg_combination_rules

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