Variant classification summary

NM_005373.2:c.1513A>T

MPL · NP_005364.1:p.(Ser505Cys) · NM_005373.2

GRCh37: chr1:43814978 A>T · GRCh38: chr1:43349307 A>T

Gene: MPL Transcript: NM_005373.2

Final call

VUS

PM1 supporting PM2 supporting PM5 supporting BP2 supporting

Variant details

Gene

MPL

Transcript

NM_005373.2

Protein

NP_005364.1:p.(Ser505Cys)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM1 (Supporting): the variant lies in the exon 10 transmembrane domain, a documented MPL mutational hotspot.

2

PM2 (Supporting): absent from gnomAD v2.1 and v4.1, an observed allele frequency of 0.

3

PM5 (Supporting): a different pathogenic change at the same codon, p.(Ser505Asn), is an established activating MPL driver.

4

BP2 (Supporting): observed in cis with the pathogenic driver W515R at a 0.37 variant allele ratio.

5

Overall: Variant of Uncertain Significance, because three supporting pathogenic criteria with no moderate or strong criterion, plus one conflicting supporting benign criterion, satisfy no pathogenic or benign combination under the generic ACMG/AMP 2015 rules.

Final determination: Generic ACMG/AMP 2015 fallback: three supporting pathogenic criteria (PM1, PM2, PM5) with no moderate or strong pathogenic criterion meet no Pathogenic or Likely Pathogenic combination, and one supporting benign criterion (BP2) meets no Benign or Likely Benign combination, 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	PVS1 not applicable: c.1513A>T is a missense change (p.Ser505Cys), so no nonsense-mediated decay or truncation mechanism applies.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not met	PS1 not met: no prior pathogenic assertion exists for p.(Ser505Cys), which is absent from ClinVar with zero submissions.	clinvar oncokb PMID:34845187 PMID:31697803
PS2	Not assessed	PS2 not assessed: no proband genotype or parental testing was available, so de novo status could not be evaluated.	PMID:34845187 PMID:31697803
PS3	Not met	PS3 not met: S505C alone produced no constitutive STAT5 activity and no factor-independent Ba/F3 growth, unlike the activating W515 controls.	PMID:34845187 PMID:31697803 oncokb
PS4	Not met	PS4 not met: no case-control comparison exists; the only documented carriers had S505C in cis with a pathogenic W515 driver.	generic_acmg_combination_rules final_classification_framework clinvar PMID:34845187 PMID:31697803
PM1	Met	PM1 met (supporting): codon 505 lies within the exon 10 transmembrane domain, a documented MPL mutational hotspot.	PMID:31697803 PMID:34845187 oncokb
PM2	Met	PM2 met (supporting): absent from gnomAD v2.1 and v4.1, an observed allele frequency of 0 versus the 0.1% threshold.	gnomad_v2 gnomad_v4 gnomad_canada clinvar pvs1_gene_context generic_acmg_combination_rules
PM3	Not met	PM3 not met: the only phase-resolved observation places S505C in cis with W515R, not in trans with a pathogenic allele.	PMID:34845187 PMID:31697803 oncokb pvs1_gene_context
PM4	N/A	PM4 not applicable: this missense change does not alter protein length, so no in-frame indel or stop-loss event applies.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Met	PM5 met (supporting): a different change at the same codon, p.(Ser505Asn), is an established pathogenic activating MPL driver.	PMID:31697803 PMID:34845187 clinvar pm5_candidates
PM6	Not assessed	PM6 not assessed: no source reports a de novo occurrence, even without confirmed parentage.	PMID:34845187 PMID:31697803
PP1	Not assessed	PP1 not assessed: no pedigree or family-member genotyping was available to count co-segregation.	PMID:34845187 PMID:31697803
PP2	Not assessed	PP2 not assessed: no gene-level missense constraint metric was available to test the low benign-missense-variation requirement.	oncokb PMID:31697803
PP3	Not met	PP3 not met: REVEL score 0.422 falls in the 0.250 to 0.750 gray zone, below the >0.750 damaging threshold.	revel
PP4	Not met	PP4 not met: no proband phenotype or family history was recorded, and the reported myeloproliferative phenotype is genetically heterogeneous. Flagged for human review: a documented proband phenotype could change this determination.	generic_acmg_combination_rules final_classification_framework oncokb pvs1_gene_context PMID:34845187 PMID:31697803
PP5	Not met	PP5 not met: no ClinGen expert-panel pathogenic classification exists, and the variant has no ClinVar record at all.	clinvar oncokb generic_acmg_combination_rules final_classification_framework
BA1	Not met	BA1 not met: allele frequency is 0 in gnomAD v2.1 and v4.1, far below the >1% stand-alone benign threshold.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
BS1	Not met	BS1 not met: with an observed allele frequency of 0, it cannot exceed the frequency expected for this rare disorder (>0.3%).	gnomad_v2 gnomad_v4 gnomad_canada pvs1_gene_context generic_acmg_combination_rules
BS2	Not met	BS2 not met: no healthy adult carrier is documented; the only reported carriers had essential thrombocythemia.	gnomad_v2 gnomad_v4 gnomad_canada clinvar PMID:34845187 PMID:31697803
BS3	Not met	BS3 not met: the assays tested only autonomous activation, and S505C measurably enhanced W515-driven STAT5 signalling rather than being functionally neutral.	PMID:34845187 PMID:31697803 oncokb
BS4	Not assessed	BS4 not assessed: no family members were genotyped, so non-segregation was never evaluated.	PMID:34845187 PMID:31697803
BP1	Not met	BP1 not met: activating missense substitutions in the exon 10 transmembrane domain are canonical MPL disease alleles.	oncokb PMID:31697803 PMID:34845187
BP2	Met	BP2 met (supporting): S505C was found in cis with the pathogenic driver W515R at a 0.37 variant allele ratio. Flagged for human review: that cis phase came from a somatic bone-marrow clone, not a constitutional sample.	PMID:34845187 PMID:31697803
BP3	N/A	BP3 not applicable: this missense change creates no in-frame indel in a repetitive region.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	BP4 not met: REVEL score 0.422 sits in the 0.250 to 0.750 gray zone, not below the <0.250 benign cutoff.	revel
BP5	Not met	BP5 not met: no alternate molecular basis for disease is documented for this proband. Flagged for human review: the proband's own molecular workup would determine applicability.	PMID:34845187 PMID:31697803 generic_acmg_combination_rules final_classification_framework
BP6	Not met	BP6 not met: no exact-variant benign classification exists; the variant has no ClinVar record, only a somatic oncogenicity label.	clinvar oncokb generic_acmg_combination_rules final_classification_framework
BP7	N/A	BP7 not applicable: this missense change alters the encoded protein sequence, so the silent-variant premise does not hold.	generic_acmg_combination_rules

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