Variant classification summary

NM_002520.7:c.860_863dup

NPM1 · NP_002511.1:p.(Trp288CysfsTer12) · NM_002520.7

GRCh37: chr5:170837543 C>CTCTG · GRCh38: chr5:171410539 C>CTCTG

Gene: NPM1 Transcript: NM_002520.7

Final call

VUS

PVS1 supporting PM2 supporting

Variant details

Gene

NPM1

Transcript

NM_002520.7

Protein

NP_002511.1:p.(Trp288CysfsTer12)

gnomAD AF

6.445940475607272e-07 (v4.1)

ClinVar

Pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

VUS: PVS1 is supporting because the terminal-exon frameshift creates p.(Trp288CysfsTer12) and is downgraded for NMD escape.

2

VUS: PM2 is supporting because the gnomAD v4.1 allele frequency is 6.445940475607272e-7 with no homozygotes.

Final determination: Under the generic ACMG/AMP 2015 fallback, two supporting criteria (PVS1 supporting and PM2 supporting) satisfy no pathogenic, likely pathogenic, benign, or likely benign rule and therefore yield VUS.

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	Met	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.	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment PMID:20026798
PS1	N/A	Not applicable: PS1 requires a missense variant, and this is a frameshift variant.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no proband-level evidence confirms both maternity and paternity, absence of family history, and a de novo germline variant.
PS3	Not assessed	Not assessed: the exact c.860_863dup was reported clinically, but no validated variant-specific functional assay was identified.	PMID:20026798 PMID:15659725 PMID:16455950 PMID:12450141
PS4	Not met	Not met: the exact variant was reported in 67 of 148 AML patients, but no valid unaffected-control comparison, odds ratio, or 95% confidence interval was reported.	PMID:20026798 gnomad_v4
PM1	N/A	Not applicable: PM1 requires a missense variant, and this is a frameshift variant.	generic_acmg_combination_rules
PM2	Met	Met at supporting: gnomAD v4.1 AF is 6.445940475607272e-7, below the <=0.0001 PM2 threshold, with no homozygotes.	gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: PM3 requires a recessive disorder, but this case provides no evidence that NPM1 c.860_863dup belongs to a recessive disorder context.	PMID:15659725 PMID:20026798
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a frameshift variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	Not applicable: PM5 requires a missense variant, and this is a frameshift variant.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no proband-level evidence supports assumed de novo occurrence without confirmed parental testing.
PP1	Not assessed	Not assessed: no affected relatives, informative meioses, or family-level variant testing are reported for co-segregation.
PP2	N/A	Not applicable: PP2 requires a missense variant, and this is a frameshift variant.	generic_acmg_combination_rules
PP3	N/A	Not applicable: c.860_863dup is a frameshift, outside PP3's generic computational-evidence scope.
PP4	Not met	Not met: AML is clinically compatible with NPM1 mutation but is not a highly specific phenotype for a single genetic etiology.	clinvar
PP5	Not met	Not met: ClinVar labels the exact variant Pathogenic, but there is no exact-variant expert-panel classification.	clinvar
BA1	Not met	Not met: gnomAD v4.1 allele frequency is 6.445940475607272e-7, far below the >=0.05 BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: the highest reported gnomAD v4.1 population AF is 1.6566165264064674e-5, below the generic 0.01 BS1 default.	gnomad_v2 gnomad_v4
BS2	Not met	Not met: gnomAD v4.1 reports 0 homozygotes, and no documented healthy-adult observation is available.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no assay directly tested c.860_863dup and demonstrated preserved NPM1 protein function or splicing.	PMID:20026798 PMID:15659725 PMID:16455950 PMID:12450141
BS4	Not assessed	Not assessed: no affected relatives or family-level testing is available to demonstrate lack of segregation.
BP1	N/A	Not applicable: BP1 requires a missense variant, and this is a frameshift variant.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no parental testing, offspring testing, or documented cis/trans relationship with a pathogenic variant is available for c.860_863dup.	PMID:15659725 PMID:20026798
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a frameshift variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	N/A	Not applicable: c.860_863dup is a frameshift, outside BP4's generic computational-evidence scope.
BP5	Not assessed	Not assessed: no alternate molecular basis for the patient’s disease is documented in the available evidence.
BP6	Not met	Not met: the exact variant has no expert-panel benign classification and is instead labeled Pathogenic by non-expert submissions.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a frameshift variant.	generic_acmg_combination_rules

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