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 ↗

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

MPL NM_005373.2

Fetching transcript structure from UCSC…

Applied criteria · 3 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

PS

PM

PP

Benign evidence

BA

BS

BP

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

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.

PMID PMID:16834459

PMID PMID:16834459 ↗

Found

Structured finding pending for this record — see source link.

Applied to

→PM1 supports · met →PS3 supports · met

PMID PMID:16868251

PMID PMID:16868251 ↗

Found

Structured finding pending for this record — see source link.

Applied to

→PM1 supports · met

PMID PMID:28823277

PMID PMID:28823277 ↗

Found

Structured finding pending for this record — see source link.

Applied to

→PS3 supports · met

Sources & reference links

7Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots