Variant classification summary

NM_003400.4:c.1711G>A

XPO1 · NP_003391.1:p.(Glu571Lys) · NM_003400.4

GRCh37: chr2:61719472 C>T · GRCh38: chr2:61492337 C>T

Gene: XPO1 Transcript: NM_003400.4

Final call

Likely Pathogenic

PS4 strong PM1 moderate PS3 supporting PM2 supporting

Variant details

Gene

XPO1

Transcript

NM_003400.4

Protein

NP_003391.1:p.(Glu571Lys)

gnomAD AF

3.1411297010147104e-06 (v4.1)

ClinVar

Likely oncogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Likely Pathogenic: PS4 strong is met by marked enrichment of E571K in PMBL versus DLBCL controls.

2

Likely Pathogenic: PM1 moderate is met because E571K is a recurrent hotspot in the XPO1 H12A NES-binding domain.

3

Likely Pathogenic: PS3 supporting is met by an altered variant-specific PMBL drug-response and apoptosis phenotype.

4

Likely Pathogenic: PM2 supporting is met because gnomAD v4.1 allele frequency is 3.14e-06 with no homozygotes.

Final determination: Under the generic ACMG/AMP 2015 fallback, one strong pathogenic criterion plus one moderate and two supporting pathogenic criteria supports 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: E571K is repeatedly reported somatically, but no previously established pathogenic classification for the same amino-acid change is documented.	PMID:21642962 PMID:27312795 PMID:27479820 clinvar oncokb
PS2	Not assessed	Not assessed: no proband phenotype, parental maternity and paternity confirmation, or germline de novo testing is reported for this variant.	PMID:27312795 PMID:27479820
PS3	Met	Met at supporting strength: E571K showed weaker KPT-185 response and apoptosis induction than wild-type XPO1 cells in a variant-specific PMBL assay.	PMID:27312795
PS4	Met	Met: XPO1 p.E571K was enriched in PMBL versus DLBCL controls, with calculated OR 29.25 and 95% CI 6.81-125.68, exceeding 5 and excluding 1.	PMID:27312795 PMID:27479820 PMID:22918138
PM1	Met	Met at moderate strength: E571K is a statistically significant hotspot in the H12A NES-binding domain, with gnomAD v4.1 AF 3.14e-6 and grpmax FAF 8e-7.	hotspots PMID:21642962 PMID:27312795 PMID:27479820 gnomad_v4
PM2	Met	Met at supporting: gnomAD v4.1 AF is 3.14e-06, below the <=0.0001 extremely-low-frequency PM2 threshold, with zero homozygotes.	gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no documented parental/offspring testing or other phase evidence establishes the variant in trans with a pathogenic variant.
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 assessed	Not assessed: p.E571G is reported at residue 571, but its pathogenic status is not established in the supplied evidence.	PMID:21642962 pm5_candidates
PM6	Not assessed	Not assessed: no germline de novo observation or parental testing is reported, and the available reports concern somatic tumor samples.	PMID:27312795 PMID:27479820
PP1	Not assessed	Not assessed: no affected relatives, informative meioses, or genotype-phenotype segregation data are reported for this variant.	PMID:27312795 PMID:27479820
PP2	Not assessed	Not assessed: no gene-level evidence establishes both low benign missense variation and a common missense disease mechanism for generic PP2.
PP3	Not met	Not met: missense REVEL score 0.579 is below the >=0.644 threshold for supporting PP3.	revel
PP4	Not assessed	Not assessed: no individual phenotype or family-history description is available to evaluate specificity for a single genetic etiology.
PP5	Not met	Not met: ClinVar has only a single-submitter Likely oncogenic assertion, not an exact-variant expert-panel Pathogenic or Likely pathogenic classification.	clinvar oncokb
BA1	Not met	Not met: gnomAD v4.1 grpmax FAF is 8e-07, far below the >=0.05 stand-alone benign threshold.	gnomad_v4
BS1	Not met	Not met: gnomAD v4.1 grpmax FAF is 8e-07, below the generic >=0.01 BS1 frequency threshold.	gnomad_v4
BS2	Not assessed	Not assessed: gnomAD reports zero homozygotes but does not document a healthy adult with the disease-relevant genotype.	gnomad_v2 gnomad_v4
BS3	Not met	Not met: E571K did not abolish nuclear export but may increase affinity for negatively charged NES sequences, so normal function was not established.	PMID:27312238 PMID:27312795
BS4	Not assessed	Not assessed: no affected-family genotypes or pedigree-based non-segregation evidence is reported for this variant.	PMID:27312795 PMID:27479820
BP1	Not assessed	Not assessed: the supplied evidence does not show that XPO1 disease is caused primarily by known truncating variants.
BP2	Not assessed	Not assessed: no documented molecular phasing establishes the variant in trans or cis with a pathogenic variant.
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 0.579 exceeds the <=0.29 threshold for supporting BP4.	revel
BP5	Not assessed	Not assessed: no case-level evidence shows the variant alongside an established alternate molecular basis for that patient's disease.
BP6	Not met	Not met: no exact-variant ClinVar expert-panel Benign or Likely benign classification is present; the only ClinVar assertion is single-submitter Likely 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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