Classification rationale

PS3PM1PM2 Likely Pathogenic

MPL c.1544G>T

The MPL c.1544G>T (p.Trp515Leu; p.W515L) variant has been reported in somatic myeloproliferative neoplasms and is listed in ClinVar with one Pathogenic submission and one Uncertain significance submission.¹ This variant is rare in population databases, with gnomAD v2.1 allele frequency 7.98378e-06 (0.00080%, 2/250508) and gnomAD v4.1 allele frequency 1.23979e-05 (0.00124%, 20/1613182), both below the 0.1% PM2 threshold.² Available functional evidence supports an abnormal activating effect, as p.W515L is described as an activating MPL variant and OncoKB classifies it as oncogenic with gain-of-function activity.³ SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.03.⁴

PS3 + PM1 + PM2 → Likely Pathogenic

1 clinvar ↗PMID:16834459 ↗PMID:16868251 ↗PMID:20113333 ↗PMID:21326037 ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 oncokb ↗PMID:16834459 ↗PMID:28823277 ↗

4 spliceai ↗

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

Gene diagram · NM_005373.2 · variants mapped to exon structure

MPL NM_005373.2

Fetching transcript structure from UCSC…

Applied criteria · 3 applied · 19 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 3

Strength Supporting Moderate Strong Very strong

PS3 review Pathogenic

Functional evidence supports a damaging effect. This variant is described as an activating MPL mutation in the literature, and OncoKB classifies p.W515L as oncogenic with gain-of-function activity, which is consistent with an abnormal functional effect relevant to disease.

OncoKB: Oncogenicbiological effect: Gain-of-function.PMID:16834459 describes MPLW515L as a somatic activating mutation.

oncokb ↗PMID:16834459 ↗PMID:28823277 ↗

PM1 review Pathogenic

This missense variant affects MPL codon Trp515, a recurrent activating site associated with myeloproliferative neoplasms. The variant has recurrent somatic observations and variant-specific oncogenic gain-of-function annotation, supporting location in a critical functional region.

OncoKB classifies p.W515L as oncogenic with gain-of-function.PMID:16834459 and PMID:16868251 report MPL W515L in myeloproliferative disease.

oncokb ↗PMID:16834459 ↗PMID:16868251 ↗

PM2 review Pathogenic

Population frequency is very low. In gnomAD v2.1 the allele frequency is 7.98378e-06 (0.00080%, 2/250508), and in gnomAD v4.1 the allele frequency is 1.23979e-05 (0.00124%, 20/1613182), with highest observed population frequency 6.683e-05 (0.00668%, East Asian) and grpmax FAF 1.772e-05; these values are all below the 0.1% PM2 threshold.

gnomAD v2.1 total AF 7.9837769652067e-062/250508 alleles0 homozygotes.

gnomad_v2 ↗gnomad_v4 ↗

Assessed · not applied · 6 not met · 13 not assessed

Pathogenic

PVS1 This is a missense variant, and the generic PVS1 framework indicates that it does not fall within the null-variant categories used for PVS1 application.

PS1 No evidence was identified here showing a different nucleotide change that results in the same amino acid substitution with an established pathogenic classification.

PS2 No confirmed de novo occurrence with verified maternity and paternity was identified.

PS4 This variant has been reported in affected myeloproliferative neoplasm cohorts, but the available evidence does not provide a germline case-control comparison sufficient to determine whether the prevalence in affected individuals is significantly increased over controls for ACMG PS4.

PM5 Other potentially relevant missense changes at codon 515 are mentioned in the literature, but a curated same-residue pathogenic comparison suitable for ACMG PM5 was not established here.

PM6 No assumed de novo occurrence without confirmed parentage was identified.

PP1 No segregation data were identified.

PP2 Available evidence does not establish a gene-specific missense mechanism or constraint pattern sufficient to apply PP2.

PP3 Computational evidence does not independently support a splice-disrupting effect.

PP4 No individual-level phenotype data were identified that would show a highly specific MPL-related presentation for this variant.

Benign

BA1 Population frequency is below the benign stand-alone threshold.

BS1 Population frequency is below the benign strong threshold.

BS2 The variant is present at very low frequency in population databases, but those observations do not establish occurrence in well-phenotyped healthy individuals sufficient for BS2.

BS3 Available functional evidence does not support a benign effect.

BS4 No nonsegregation data were identified.

BP2 No phase data with another pathogenic variant were identified.

BP3 No evidence was identified showing that this variant lies in a repetitive region without known function.

BP4 Computational evidence does not support a benign splice effect.

BP5 No alternate molecular explanation for the observed disease was identified.

N/A · 6 PM3 · PM4 · PP5 · BP1 · BP6 · BP7

Research & evidence

Population frequency · supports pathogenic

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 1.23979e-05; MAF= 0.00124%, 20/1613182 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 6.683e-05; MAF= 0.00668%, 3/44890 alleles, homozygotes = 0); grpmax FAF= 1.772e-05.

v2.1

This variant is present in gnomAD v2.1 (AF= 7.98378e-06; MAF= 0.00080%, 2/250508 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 6.15612e-05; MAF= 0.00616%, 1/16244 alleles, homozygotes = 0).

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0012% · 20 / 1,613,182
0 hom · FAF 0.0018%

East Asian 3 / 44,890	0.0067%
Ashkenazi Jewish 1 / 29,590	0.0034%
European (Finnish) 1 / 63,282	0.0016%
African/African American 1 / 74,922	0.0013%
European (non-Finnish) 13 / 1,179,942	0.0011%
South Asian 1 / 91,094	0.0011%

+ 4 not observed (Remaining individuals, Admixed American, Amish, Middle Eastern)

gnomAD v2.1

0.0008% · 2 / 250,508
0 hom

African/African American 1 / 16,244	0.0062%
East Asian 1 / 18,378	0.0054%

+ 6 not observed (Admixed American, Ashkenazi Jewish, European (Finnish), European (non-Finnish), Remaining individuals, South Asian)

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Pathogenic (1 clinical laboratory) and as Uncertain significance (1 clinical laboratory).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03).

SpliceAI ↗

Functional Oncogenic

OncoKB classifies this variant as Oncogenic; biological effect: Gain-of-function.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV65243776, n = 277 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Literature · how each cited paper was used

3papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.

MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid me

PMID 16834459 ↗

Found

and PMID:16868251 report MPL W515L in myeloproliferative disease.

Applied to

→PS3 met

→PM1 met

MPL515 mutations in myeloproliferative and other myeloid disorders: a study of 1

PMID 16868251 ↗

Found

and PMID:16868251 report MPL W515L in myeloproliferative disease.

Applied to

→PM1 met

[AKT Is A Therapeutic Target in Myeloproliferative Neoplasms].

PMID 28823277 ↗

Found

reports constitutive pathway activation in an MPL W515L model.

Applied to

→PS3 met

Sources & reference links

7Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

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