Variant classification summary

NM_005373.3:c.1544G>T

MPL · NP_005364.1:p.(Trp515Leu) · NM_005373.3

GRCh37: chr1:43815009 G>T · GRCh38: chr1:43349338 G>T

Gene: MPL Transcript: NM_005373.3

Final call

Pathogenic

PS1 strong PS3 strong PM1 moderate PM2 supporting PM5 moderate

Variant details

Gene

MPL

Transcript

NM_005373.3

Protein

NP_005364.1:p.(Trp515Leu)

gnomAD AF

1.2397857154369438e-05 (v4.1)

ClinVar

Pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Pathogenic: PS1 strong establishes the same pathogenic MPL p.Trp515Leu amino-acid change.

2

Pathogenic: PS3 strong demonstrates activating MPL W515L effects in cellular and mouse assays.

3

Pathogenic: PM1 moderate identifies codon 515 as a recurrent MPL mutational hotspot.

4

Pathogenic: PM2 supporting shows gnomAD v4.1 grpmax FAF below 0.0001.

5

Pathogenic: PM5 moderate documents a pathogenic alternate missense change at residue 515.

Final determination: Under the generic ACMG/AMP 2015 fallback, two strong pathogenic criteria plus two moderate pathogenic criteria satisfy the Pathogenic combination rule; the additional supporting PM2 is concordant.

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	Met	Met: MPL p.Trp515Leu was previously established as pathogenic and activating, with cytokine-independent growth and a lethal myeloproliferative phenotype.	PMID:16834459 clinvar
PS2	Not assessed	Not assessed: no proband-specific trio testing confirms both maternity and paternity, and no documented absence of family history is available.	PMID:16834459 PMID:16868251 PMID:21326037
PS3	Met	Met, strong: MPL W515L caused cytokine-independent growth, constitutive signaling, and lethal myeloproliferative disease across cellular and mouse assays.	PMID:16834459
PS4	Not met	Not met: 17/1,182 cases versus 0/64 controls gives an infinite crude OR, but the available counts do not establish a 95% CI excluding 1.	PMID:16868251
PM1	Met	Met: W515L accounted for 46/68 MPL mutations (67.7%), establishing codon 515 as a recurrent disease-associated mutational hotspot without a reported benign codon-515 observation.	PMID:21326037 PMID:16868251
PM2	Met	Met at supporting: gnomAD v4.1 grpmax FAF is 1.772e-05, below the generic PM2 threshold of 0.0001.	gnomad_v4 gnomad_v2
PM3	Not assessed	Not assessed: no affected-proband observation with a pathogenic variant in trans and no parental or offspring testing establishes phase.	PMID:16834459 clinvar
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	Met	Met: the alternate missense p.Trp515Lys was reported in five affected patients at residue 515 in a study describing MPL515 changes as gain-of-function mutations.	PMID:16868251
PM6	Not assessed	Not assessed: no proband-specific observation supports an assumed de novo variant, with or without parental confirmation.	PMID:16834459 PMID:16868251 PMID:21326037
PP1	Not assessed	Not assessed: zero informative affected relatives or meioses are documented for cosegregation of the variant with disease.	PMID:16834459 PMID:16868251 PMID:21326037
PP2	Not assessed	Not assessed: no gene-wide benign-missense rate and no governing evidence that missense variants are the common MPL disease mechanism were available.
PP3	Not met	Not met: missense REVEL score 0.328 is below the >=0.644 supporting PP3 threshold.	revel
PP4	Not assessed	Not assessed: the current patient’s phenotype and family history are not available to determine whether they are highly specific for a single-gene disease.
PP5	Not met	Not met: no exact-variant ClinVar expert-panel pathogenic classification exists, and the underlying literature is available for independent evaluation.	clinvar
BA1	Not met	Not met: gnomAD v4.1 grpmax FAF is 1.772e-05, far below the generic BA1 threshold of 0.05.	gnomad_v4 clinvar PMID:16834459
BS1	Not met	Not met: gnomAD v4.1 grpmax FAF is 1.772e-05, below the generic BS1 default of 0.01.	gnomad_v4
BS2	Not assessed	Not assessed: no homozygotes were observed, and gnomAD carrier observations cannot establish constitutional healthy-adult status for this somatic variant.	gnomad_v2 gnomad_v4 PMID:16834459
BS3	Not met	Not met: Normal platelet MPL expression and STAT phosphorylation do not demonstrate absence of damage, and direct cellular and mouse assays show MPL W515L gain of function.	PMID:20113333 PMID:16834459
BS4	Not assessed	Not assessed: no affected-family genotype data are available to demonstrate lack of segregation.	PMID:16834459 PMID:16868251 PMID:21326037
BP1	Not assessed	Not assessed: the evidence does not show that disease-causing MPL variants are primarily truncating rather than missense.
BP2	Not assessed	Not assessed: no confirmed pathogenic cis or trans partner is phase-established by parental, offspring, or haplotype testing.	PMID:16834459 PMID:16868251 clinvar
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 0.328 exceeds the <=0.29 supporting BP4 threshold and is indeterminate.	revel
BP5	Not assessed	Not assessed: no case-level alternate molecular diagnosis is documented for determining whether the variant occurred with another disease cause.
BP6	Not met	Not met: no exact-variant ClinVar expert-panel benign classification is present, and no qualifying unavailable benign evidence was identified.	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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