The NPM1 NM_002520.7:c.860_863dup (NP_002511.1:p.(Trp288CysfsTer12)) frameshift variant has previously been reported in somatic cancers (COSMIC; COSV51542664, n = 3293 times). Based on available guidelines, this variant is considered to be a Variant of Uncertain Significance (VUS).
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.NPM1 encodes nucleophosmin, a protein that helps regulate ribosome production, cell growth, DNA repair, and the movement and stability of other cellular proteins. It also helps control the tumor-suppressor pathways involving ARF and TP53. NPM1 is strongly associated with acute myeloid leukemia and can act as both a tumor suppressor and an oncogene in blood cancers.
The recorded framework is Generic ACMG/AMP 2015 with ClinGen SVI recommendations. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
The applied criteria and their strengths are shown as assessed under the stated framework.
Met at supporting strength: the exon 11 frameshift creates p.(W288Cfs*12) and a stop in the terminal exon, triggering the named NMD-escape downgrade.
Met at supporting: gnomAD v4.1 AF is 6.445940475607272e-7, below the <=0.0001 PM2 threshold, with no homozygotes.
No benign criterion marked as applied in the recorded assessment.
VUS: PVS1 (supporting) plus PM2 (supporting) do not satisfy any generic ACMG/AMP 2015 pathogenic, likely pathogenic, benign, or likely benign combination.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 1 / 1,551,364 alleles. Recorded AF 6.44594e-07. Recorded homozygote count 0.
Absent from gnomAD v2.1.
Absent from gnomAD-Canada v1.0.
Recorded SpliceAI maximum delta score: 0.002. Refer to the recorded PP3/BP4 rationale for interpretation.
3 Pathogenic. ClinVar API review status: criteria provided, single submitter.
OncoKB identified variant-specific curated literature and context relevant to functional review; curated oncogenicity label: Oncogenic.
This variant has previously been reported in somatic cancers (COSMIC; COSV51542664, n = 3293 times).
This variant does not lie in a statistically significant hotspot.
ACMG/AMP criteria under Generic ACMG/AMP 2015 with ClinGen SVI recommendations, with the data and sources behind each one.
28 criteria with recorded statuses: 2 met · 7 not met · 8 not assessed · 11 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
No segregation, non-segregation, or proband-level parental-testing evidence was identified for PS2, PM6, PP1, or BS4; all four criteria are not assessed.
No VCEP covers NPM1, so generic ACMG/AMP 2015 rules govern.
The exact variant is documented in an AML cohort, but the available report is not a valid case-control study for PS4.
The exact ClinVar record has no expert-panel submission; non-expert Pathogenic assertions do not trigger PP5 or BP6 under the specified rule.
Population evidence supports PM2 at supporting strength because the variant is absent from gnomAD v2.1 and non-cancer subsets and has gnomAD v4.1 AF=6.445940475607272e-7, while BA1, BS1, and BS2 are not met.
No criteria match.
NM_002520.7:c.860_863dup is a frameshift variant in the relevant MANE transcript NM_002520.7, producing NP_002511.1:p.(Trp288CysfsTer12). The gene-level PVS1 gate is eligible in the generic framework. The variant is in exon 11, the terminal exon of this transcript, and the predicted stop occurs within that terminal exon; this is a named NMD-escape downgrade from the default very-strong level. The altered C-terminal protein sequence is not an in-frame repeat-region indel, and no non-critical-exon downgrade was applied. PVS1 is therefore met at supporting strength rather than very strong strength.
PVS1: Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
PM2 at supporting strength is met. The variant is absent from gnomAD v2.1 and the gnomAD v2.1 non-cancer exome subset, and is absent from gnomAD v3.1 non-cancer genomes (0/146,260 alleles). In gnomAD v4.1 all-comers it is observed once among 1,551,364 alleles (AF=6.445940475607272e-7), which is below the generic PM2 supporting threshold of <=0.0001; no homozygotes are observed. The indel-calling caveat applies, but concordant rarity across the available datasets supports PM2.
PM2 (supporting): <= 0.0001 — SVI recommendation to downgrade PM2 to Supporting (ClinGen SVI 2020) (PMID:25741868)
No qualifying case-control enrichment study was identified for the exact variant NM_002520.7:c.860_863dup. PMID:20026798 reports the exact duplication in 67 of 83 NPM1-mutated patients and 67 of 148 older adults with cytogenetically normal AML, but provides no unaffected or population control count and does not establish a germline case-control comparison. The available gnomAD frequency is 1/1,551,364 alleles, but comparison of a somatic AML frequency with a germline population frequency is not a valid matched case-control estimate for this criterion; therefore no valid OR and 95% CI were calculated. The PS4-indexed PMIDs 20963938, 23970018, 32171751, and 33226740 are not relevant exact-variant case-control reports in the reviewed literature packet.
The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. ... Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0.
The documented phenotype is acute myeloid leukemia or myelodysplastic syndrome progressed to acute myeloid leukemia. This phenotype is not highly specific for a single genetic etiology because AML has many molecular causes, and the supplied evidence does not establish a distinctive phenotype that specifically identifies NPM1-related disease for this variant.
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
The exact ClinVar record is classified Pathogenic, but it has no expert-panel submission. The available assertions are ordinary laboratory, research, or literature-only submissions, including single-submitter clinical-testing assertions, so the required exact-variant ClinVar expert-panel classification is absent and PP5 is not applied.
Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.
BA1 is not met. The variant's highest reported all-comers frequency is 6.445940475607272e-7 (1/1,551,364 alleles) in gnomAD v4.1, with 0 homozygotes; this is far below the generic BA1 stand-alone threshold of >=0.05. The gnomAD v2.1 and v2.1 non-cancer exome datasets report the variant as absent, and gnomAD v3.1 non-cancer genomes report 0/146,260 alleles. The variant is an indel, so the ACMG/AMP caveat about potentially poor indel calling applies, but the available multi-dataset observations do not support BA1.
BA1 (stand-alone): >= 0.05 — ACMG/AMP 2015 stand-alone benign allele frequency (PMID:25741868)
BS1 is not met. The observed all-comers gnomAD v4.1 AF is 6.445940475607272e-7 and the highest reported population AF is 1.6566165264064674e-5, both far below the generic 0.01 default. The variant is absent from gnomAD v2.1 and gnomAD v2.1 non-cancer exomes, and has AF=0 in gnomAD v3.1 non-cancer genomes. These frequencies are not greater than expected for a disorder; no maximum-credible-frequency calculation is needed because the observed frequency is orders of magnitude below the default threshold.
BS1: Allele frequency is greater than expected for the disorder.
BS2 is not met. No homozygous individuals were observed in gnomAD v4.1 (0 homozygotes), gnomAD v3.1 non-cancer genomes (0 homozygotes), or the available gnomAD v2.1 datasets, and no healthy adult observation of this variant is documented in the population evidence. Therefore the required observation in a healthy adult individual is not present.
Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.
ClinVar does not provide an exact-variant expert-panel benign or likely benign classification. Instead, the exact record is classified Pathogenic by non-expert submissions, so the required evidence for BP6 is absent and the contradictory pathogenic label cannot trigger BP6.
Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.
The available evidence identifies the variant in AML cohorts, including a study of de novo AML, but does not provide a proband-level germline case with confirmed maternity and paternity, absence of family history, and phenotype documentation. The phrase de novo AML describes disease presentation and is not evidence that the variant arose de novo. Therefore PS2 cannot be assessed.
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
The exact variant is reported as the NPM1 type A c.860_863dup in PMID:20026798, but that study reports cohort detection and clinical outcomes rather than a functional assay. Functional studies in PMID:15659725 and PMID:16455950 evaluated NPM1 exon-12 mutant constructs or related mutations and showed abnormal cytoplasmic localization, but the supplied extractions do not establish that the exact c.860_863dup construct was tested. Therefore, the available evidence does not establish a well-established, variant-specific in vitro or in vivo assay supportive of a damaging effect, and PS3 cannot be assigned.
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
The available evidence does not document an assumed de novo variant in a specific proband. No parental testing, family-history information, or proband-level germline inheritance assessment is provided. The reported de novo AML cohort does not establish de novo occurrence of this variant. Therefore PM6 cannot be assessed.
Assumed de novo, but without confirmation of paternity and maternity.
No family pedigree, affected relatives, variant testing in relatives, or meioses are reported for this variant. The available cohort evidence is not segregation evidence and does not establish co-segregation in affected family members. Therefore PP1 cannot be assessed.
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease. ... Note: May be used as stronger evidence with increasing segregation data.
No well-established functional study in the supplied evidence demonstrates that NPM1 c.860_863dup/p.(W288Cfs*12) has no damaging effect on protein function or splicing. The exact variant is clinically reported in PMID:20026798 without a normal-function assay, while the available NPM1 localization studies concern other or incompletely matched mutant constructs and show abnormal localization rather than preserved function. Thus BS3 cannot be assigned.
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
No affected family members, tested relatives, non-segregating relatives, or family pedigree are documented. Consequently, there is no evidence of lack of segregation and no basis to evaluate the phenocopy or multiple-pathogenic-variant caveat. Therefore BS4 cannot be assessed.
Lack of segregation in affected members of a family. ... Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals.
The BP2 rule requires observation in trans with a pathogenic variant for a fully penetrant dominant disorder or in cis with a pathogenic variant in any inheritance pattern. The available evidence does not document parental or offspring testing, cis/trans phase, or a second pathogenic variant in the same individual. The exact-variant AML report provides no segregation or phase data, and the other reviewed AML report describes heterozygosity in the malignant clone without identifying a pathogenic partner allele.
Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.
The supplied evidence documents AML and the exact NPM1 variant, but does not document an alternate molecular basis for disease in the same case. No second pathogenic variant, established alternate diagnosis, or other alternate molecular etiology is available to assess BP5.
Variant found in a case with an alternate molecular basis for disease.
PS1 (Richards et al. 2015, PMID:25741868) requires the same amino acid change as a previously established pathogenic variant, evaluated regardless of the underlying nucleotide change. NM_002520.7:c.860_863dup in NPM1 is a frameshift variant predicted to produce NP_002511.1:p.(Trp288CysfsTer12). As a result, no altered amino acid exists at this position to compare against any previously established pathogenic missense variant, so PS1's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PS1 for NPM1, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_missense
PM1 (Richards et al. 2015, PMID:25741868) applies to a missense variant located in a mutational hot spot and/or a critical, well-established functional domain without benign variation. NM_002520.7:c.860_863dup in NPM1 is a frameshift variant predicted to produce NP_002511.1:p.(Trp288CysfsTer12). As a result, no altered residue exists to evaluate for mutational hot-spot or critical-domain membership, so PM1's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PM1 for NPM1, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_missense
PM3 is limited to recessive disorders and requires the variant to be detected in trans with a pathogenic variant. The available case evidence describes NPM1 c.860_863dup in somatic AML and does not establish a recessive NPM1 disorder; therefore PM3 is not applicable.
For recessive disorders, detected in trans with a pathogenic variant ... This requires testing of parents (or offspring) to determine phase.
PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_002520.7:c.860_863dup in NPM1 is a frameshift variant predicted to produce NP_002511.1:p.(Trp288CysfsTer12). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PM4 for NPM1, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel
PM5 (Richards et al. 2015, PMID:25741868) requires a novel missense change at an amino acid residue where a different missense change has previously been determined to be pathogenic. NM_002520.7:c.860_863dup in NPM1 is a frameshift variant predicted to produce NP_002511.1:p.(Trp288CysfsTer12). As a result, no missense change exists at this residue to compare against a different pathogenic missense change at the same position, so PM5's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PM5 for NPM1, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_missense
PP2 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene with a low rate of benign missense variation, where missense variants are a common mechanism of disease. NM_002520.7:c.860_863dup in NPM1 is a frameshift variant predicted to produce NP_002511.1:p.(Trp288CysfsTer12). As a result, the gene's missense-constraint properties are irrelevant because no missense change is present to evaluate, so PP2's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PP2 for NPM1, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_missense
PP3 is not applicable because NM_002520.7:c.860_863dup is an exonic frameshift variant, predicted to produce NP_002511.1:p.(Trp288CysfsTer12). The generic PP3 computational path applies to missense variants through REVEL or intronic, synonymous, and splice-region variants through SpliceAI; it does not apply to frameshift or other truncating/protein-length-changing variants. The available SpliceAI max delta of 0.002 is therefore not used for PP3.
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
BP1 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene for which primarily truncating variants are known to cause disease. NM_002520.7:c.860_863dup in NPM1 is a frameshift variant predicted to produce NP_002511.1:p.(Trp288CysfsTer12). As a result, the gene's truncating-variant mechanism is irrelevant because no missense change is present to evaluate, so BP1's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP1 for NPM1, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_missense
BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_002520.7:c.860_863dup in NPM1 is a frameshift variant predicted to produce NP_002511.1:p.(Trp288CysfsTer12). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP3 for NPM1, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_repeat_region_indel
BP4 is not applicable because NM_002520.7:c.860_863dup is an exonic frameshift variant, predicted to produce NP_002511.1:p.(Trp288CysfsTer12). A no-impact splice prediction cannot negate the truncating protein effect, and the generic BP4 computational path does not apply to frameshift or other truncating/protein-length-changing variants. The available SpliceAI max delta of 0.002 is therefore not used for BP4.
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_002520.7:c.860_863dup in NPM1 is a frameshift variant predicted to produce NP_002511.1:p.(Trp288CysfsTer12). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for NPM1, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
Every interpreted variant in NPM1, mapped onto the exon structure of NM_002520.7. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| Remaining individuals1 / 60,364 | 1.7e-05 |
This variant is present in gnomAD v4.1 (AF= 6.44594e-07; MAF= 0.00006%, 1/1551364 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 1.65662e-05; MAF= 0.00166%, 1/60364 alleles, homozygotes = 0).
Absent from gnomAD v2.1.
Absent from gnomAD-Canada v1.0.
PP3 is not applicable because NM_002520.7:c.860_863dup is an exonic frameshift variant, predicted to produce NP_002511.1:p.(Trp288CysfsTer12). The generic PP3 computational path applies to missense variants through REVEL or intronic, synonymous, and splice-region variants through SpliceAI; it does not apply to frameshift or other truncating/protein-length-changing variants. The available SpliceAI max delta of 0.002 is therefore not used for PP3.
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
BP4 is not applicable because NM_002520.7:c.860_863dup is an exonic frameshift variant, predicted to produce NP_002511.1:p.(Trp288CysfsTer12). A no-impact splice prediction cannot negate the truncating protein effect, and the generic BP4 computational path does not apply to frameshift or other truncating/protein-length-changing variants. The available SpliceAI max delta of 0.002 is therefore not used for BP4.
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_002520.7:c.860_863dup in NPM1 is a frameshift variant predicted to produce NP_002511.1:p.(Trp288CysfsTer12). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for NPM1, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
7 paper records listed. 1 cited in the classification.
The most frequent was a type A mutation (n = 67 [81%]), that is, the duplication of TCTG at position c.860_863.
Location Results, "Clinical Characteristics and Molecular Markers at Diagnosis"
Context Pretreatment bone marrow samples from 148 adults aged 60 years or older with de novo cytogenetically normal AML; NPM1 exon 12 was PCR-amplified and directly sequenced using reference sequences NM_002520.5 and NP_002511.1.
Six sequence variants were observed, all leading to a frame shift in the region encoding the C-terminal of the NPM protein.
Results, "Mutations in NPM exon 12 in NPMc+ AML," pp. 261–263; Figure 4
These results suggest that tryptophans 288 and 286 in protein B23.1 were important for its nucleolar localization.
Results, p. 2242; Fig. 3C
All 29 AML-associated mutated NPM alleles so far identified encode abnormal proteins which have acquired at the C-terminus a nuclear export signal (NES) motif and lost both tryptophan residues 288 and 290 (or only the residue 290) which determine nucleolar localization. We show for the first time that both alterations are crucial for NPM mutant export from nucleus to cytoplasm.
Abstract; Results, "Export of NPM leukemic mutants is NES dependent" and "Role of tryptophans 288 and 290 in nucleolar binding and nuclear export of NPM leukemic mutants"; Table 1
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The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
This variant is present in gnomAD v4.1 (AF= 6.44594e-07; MAF= 0.00006%, 1/1551364 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 1.65662e-05; MAF= 0.00166%, 1/60364 alleles, homozygotes = 0).
Absent from gnomAD v2.1.
Absent from gnomAD-Canada v1.0.
This variant has been reported in ClinVar as Pathogenic (3 clinical laboratories). (ClinVarID = 13998)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
OncoKB identified variant-specific curated literature and context relevant to functional review; curated oncogenicity label: Oncogenic.
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV51542664, n = 3293 times).
This variant does not lie in a statistically significant hotspot.