About MYD88
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
MYD88 c.818T>C, p.(Leu273Pro)
Classification
Pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.
Pathogenic.A pathogenic classification under the recorded framework.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
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Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 5
Benign evidence criteria: 0
Pathogenic criteria applied · 5
PS3Strong
PS3 · strong
Well-established functional studies from multiple independent groups demonstrate that MYD88 L273P (canonical L265P) constitutively activates NF-kappaB and JAK/STAT signaling, confers IL-6 and IL-10 autocrine survival, and that knockdown or inhibition of the mutant protein is selectively toxic to MYD88-mutant lymphoma cells. This gain-of-function mechanism is consistent with the known disease mechanism in Waldenstrom macroglobulinemia and ABC DLBCL.
PS4Strong
PS4 · strong
The variant is highly enriched in affected individuals compared to general population controls. MYD88 L273P (L265P) is detected in approximately 90% of Waldenstrom macroglobulinemia cases and is recurrent in ABC DLBCL and IgM-MGUS. In contrast, it is extremely rare in gnomAD (v2.1 AF=5.17e-05, 13/251,436 alleles; v4.1 AF=2.60e-05, 42/1,614,060 alleles; zero homozygotes). COSMIC reports 2,493 independent tumor samples with this variant. The odds ratio substantially exceeds the threshold for PS4_strong.
PM1Moderate
PM1 · moderate
The variant affects codon 273 within the TIR domain BB-loop, a critical functional domain essential for MYD88 signal transduction and a well-established mutational hotspot. COSMIC reports 2,493 independent samples with mutations in this domain.
PM2Supporting
PM2 · supporting
The variant is extremely rare in population databases. gnomAD v2.1 allele frequency is 5.17e-05 (0.00517%, 13/251,436 alleles), and v4.1 allele frequency is 2.60e-05 (0.00260%, 42/1,614,060 alleles), both well below the 0.1% PM2 threshold. Zero homozygotes observed. gnomAD-Canada shows no data.
PP3Supporting
PP3 · supporting
Multiple lines of in silico computational evidence support a deleterious effect. REVEL score is 0.735 (above the 0.5 threshold for pathogenicity). BayesDel score is 0.13148 (borderline/low). SpliceAI predicts no splicing impact (max delta = 0.0). The REVEL score provides supporting evidence for pathogenicity, though BayesDel is not strongly corroborative.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Pathogenic
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PS3 strong, PS4 strong, PM1 moderate, PM2 supporting, PP3 supporting; combination = 2 strong + 1 moderate + 2 supporting, which maps to Pathogenic.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
42 / 1,614,060 alleles
gnomAD v4.1: 42 / 1,614,060 alleles. Recorded AF 2.60213e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 5.1703e-05; MAF= 0.00517%, 13/251436 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.000397219; MAF= 0.03972%, 4/10070 alleles, homozygotes = 0); grpmax FAF= 3.419e-05.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
2 reported laboratory submissions
1 Uncertain significance · 1 Likely pathogenic.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. MYD88, an adaptor protein, is frequently altered in hematologic malignancies including Waldenström's macroglobulinemia.
COSMIC
Cancer Hotspots
Somatic evidence
2493 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV57169334, n = 2493 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
29 criteria with recorded statuses: 5 met · 14 not met · 2 not assessed · 8 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
MYD88 c.818T>C (p.Leu273Pro), corresponding to the canonical L265P mutation, is a well-characterized gain-of-function missense variant in the TIR domain BB-loop (PM1_moderate).
Multiple independent functional studies demonstrate that this variant constitutively activates NF-kappaB and JAK/STAT signaling, confers cytokine-independent survival, and that mutant-specific knockdown or pharmacologic inhibition is selectively toxic to MYD88-mutant cells (PS3_strong).
The variant is highly enriched in affected individuals, detected in approximately 90% of Waldenstrom macroglobulinemia cases and recurrent in ABC DLBCL and IgM-MGUS, compared to an extremely low population frequency of 0.0026-0.0052% in gnomAD with zero homozygotes (PS4_strong).
The variant is absent or extremely rare in population databases, with gnomAD v2.1 AF=5.17e-05 and v4.1 AF=2.60e-05, both well below the 0.1% threshold (PM2_supporting).
In silico predictors support a deleterious effect: REVEL score of 0.735 exceeds the pathogenicity threshold of 0.5, though BayesDel (0.13148) is borderline and SpliceAI predicts no splicing impact (PP3_supporting).
All benign criteria were assessed and none were met. BS3 is specifically contradicted by well-established functional evidence of a gain-of-function damaging effect. BA1 and BS1 are not met as population frequencies remain well below benign thresholds.
Applying generic ACMG/AMP 2015 combination rules: 2 Strong (PS3, PS4) + 1 Moderate (PM1) + 2 Supporting (PM2, PP3) meets the threshold for Pathogenic (>=2 Strong).
CAVEAT: The evidence supporting PS3_strong and PS4_strong derives predominantly from somatic tumor studies. The variant is almost exclusively observed as a somatic mutation in hematologic malignancies. The germline ACMG/AMP framework is being applied to a variant with a somatic disease mechanism. Classification should be interpreted with this context, and human review is recommended to confirm the appropriateness of this germline-classification for the clinical indication.
No criteria match.
Met · 5
PS3 StrongWell-established functional studies from multiple independent groups demonstrate that MYD88 L273P (canonical L265P) constitutively activates NF-kappaB and JAK/STAT signaling, confers IL-6 and IL-10 autocrine survival, and that knockdown or inhibition of the mutant protein is selectively toxic to MYD88-mutant lymphoma cells. This gain-of-function mechanism is consistent with the known disease mechanism in Waldenstrom macroglobulinemia and ABC DLBCL. Details ▾Hide ▴
Evidence considered
- Ngo et al. 2011 (PMID:21179087): MYD88 L265P identified in ABC DLBCL
- constitutively activates NF-kappaB and JAK/STAT
- knockdown kills mutant cells.
- Yang et al. 2013 (PMID:23836557): MYD88 L265P activates BTK and NF-kappaB
- BTK inhibition reduces survival of L265P-expressing lymphoplasmacytic cells.
- Treon et al. 2012 (PMID:22931316): MYD88 L265P found in >90% of WM
- NF-kappaB activation confirmed in primary cells.
Still missing
- Functional studies performed in somatic/cancer context
- germline-specific functional data not available.
Sources
PS4 StrongThe variant is highly enriched in affected individuals compared to general population controls. MYD88 L273P (L265P) is detected in approximately 90% of Waldenstrom macroglobulinemia cases and is recurrent in ABC DLBCL and IgM-MGUS. In contrast, it is extremely rare in gnomAD (v2.1 AF=5.17e-05, 13/251,436 alleles; v4.1 AF=2.60e-05, 42/1,614,060 alleles; zero homozygotes). COSMIC reports 2,493 independent tumor samples with this variant. The odds ratio substantially exceeds the threshold for PS4_strong. Details ▾Hide ▴
Evidence considered
- PMID:22931316: L265P in >90% of WM by whole-genome sequencing of 30 patients.
- PMID:23355535: L265P in 96% of WM
- 54% of IgM-MGUS by allele-specific PCR.
- PMID:23215570: L265P identified in IgM-MGUS.
- gnomAD v2.1: AF=5.17e-05 (13/251
- 436 alleles).
- gnomAD v4.1: AF=2.60e-05 (42/1
- 614
- 060 alleles).
- COSMIC: COSV57169334
- n=2
- 493 samples.
Still missing
- Case-control data are from somatic tumor-vs-normal comparisons
- not classical germline case-control studies. PS4 is being applied to predominantly somatic prevalence data under the generic ACMG framework.
Sources
PM1 ModerateThe variant affects codon 273 within the TIR domain BB-loop, a critical functional domain essential for MYD88 signal transduction and a well-established mutational hotspot. COSMIC reports 2,493 independent samples with mutations in this domain. Details ▾Hide ▴
Evidence considered
- Residue L273 is located in the TIR domain BB-loop
- a critical region for MYD88-mediated signaling.
- COSMIC: 2
- 493 samples with variants at this locus
- confirming hotspot status.
Still missing
- No ClinGen MYD88 VCEP exists to provide domain-level PM1 specifications.
Sources
PMID:23215570 ↗23215570
PM2 SupportingThe variant is extremely rare in population databases. gnomAD v2.1 allele frequency is 5.17e-05 (0.00517%, 13/251,436 alleles), and v4.1 allele frequency is 2.60e-05 (0.00260%, 42/1,614,060 alleles), both well below the 0.1% PM2 threshold. Zero homozygotes observed. gnomAD-Canada shows no data. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: AF=5.17e-05 (13/251
- 436 alleles
- 0 homozygotes).
- gnomAD v4.1: AF=2.60e-05 (42/1
- 614
- 060 alleles
- gnomAD-Canada: absent (no data).
Sources
PP3 SupportingMultiple lines of in silico computational evidence support a deleterious effect. REVEL score is 0.735 (above the 0.5 threshold for pathogenicity). BayesDel score is 0.13148 (borderline/low). SpliceAI predicts no splicing impact (max delta = 0.0). The REVEL score provides supporting evidence for pathogenicity, though BayesDel is not strongly corroborative. Details ▾Hide ▴
Evidence considered
- REVEL: 0.735 (deleterious
- >0.5 threshold).
- BayesDel: 0.13148 (borderline
- below typical damaging threshold of ~0.27).
- SpliceAI: max delta = 0.0 (no splicing impact predicted).
Still missing
- BayesDel score is borderline/low and does not independently support PP3
- weight is placed primarily on REVEL.
Sources
Not met · 14 · evaluated, threshold not reached
PS2 No confirmed de novo germline occurrence (with both maternity and paternity confirmed) has been reported for this variant. MYD88 c.818T>C (p.L273P/L265P) is predominantly a somatic gain-of-function mutation in hematologic malignancies, and germline de novo events are not described in the literature. Details ▾Hide ▴
Evidence considered
- No de novo germline reports identified in ClinVar or literature.
Still missing
- No germline de novo studies available
- variant is primarily somatic.
Sources
2117908722931316
PM6 No evidence of assumed de novo occurrence (without confirmation of paternity and maternity). MYD88 c.818T>C is a somatic mutation; germline de novo events are not reported. Details ▾Hide ▴
Evidence considered
- No de novo germline observations in the literature or ClinVar.
Still missing
- No germline de novo studies available.
PP1 No cosegregation data available. MYD88-related malignancies (Waldenstrom macroglobulinemia, DLBCL) are sporadic somatic diseases; familial cosegregation studies are not applicable to a somatic mutation. Details ▾Hide ▴
Evidence considered
- No cosegregation data in the literature. Disease is sporadic/somatic.
Still missing
- Cosegregation not applicable to somatic mutation context.
PP5 The only ClinVar submission with assertion criteria provided (Labcorp Genetics, SCV000767876) classifies this variant as Uncertain Significance, not Pathogenic. Other submissions (OMIM: Pathogenic, Wasik Lab: Likely Pathogenic) lack assertion criteria. PP5 requires a reputable source to have reported the variant as pathogenic without the evaluating laboratory having access to the primary evidence. Details ▾Hide ▴
Evidence considered
- ClinVar SCV000767876 (Labcorp): Uncertain significance (criteria provided
- single submitter).
- ClinVar SCV000053370 (OMIM): Pathogenic (no assertion criteria provided).
- ClinVar SCV004020299 (Wasik Lab): Likely pathogenic (no assertion criteria provided).
Still missing
- No criteria-provided submission classifies this as pathogenic in the germline context.
Sources
BA1 Allele frequency is well below the 1% threshold for BA1. gnomAD v2.1 AF = 5.17e-05 (0.00517%); gnomAD v4.1 AF = 2.60e-05 (0.00260%). The variant is not a common polymorphism. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF = 5.17e-05 << 1%.
- gnomAD v4.1 AF = 2.60e-05 << 1%.
Sources
BS1 Allele frequency is below the 0.3% threshold for BS1. gnomAD v2.1 AF = 0.00517%; gnomAD v4.1 AF = 0.00260%. The variant is not observed at a frequency compatible with a benign interpretation. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF = 0.00517% << 0.3%.
- gnomAD v4.1 AF = 0.00260% << 0.3%.
Sources
BS2 Although the variant is observed at very low frequency in gnomAD (presumed healthy population controls: 13-42 heterozygous carriers), this observation is at an allele frequency of 0.0026-0.0052%, which is far below the threshold for BS2. Late-onset hematologic malignancies would not manifest in healthy young adult carriers. The low-frequency gnomAD observation does not constitute sufficient evidence of benign observation in healthy adults. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 13 heterozygous carriers (no homozygotes).
- gnomAD v4.1: 42 heterozygous carriers (no homozygotes).
- WM is a late-onset disease
- healthy young carriers may be pre-symptomatic.
Sources
BS3 Well-established functional studies demonstrate that MYD88 L273P (L265P) has a gain-of-function damaging effect (constitutive NF-kappaB activation, JAK/STAT signaling, cytokine secretion), not a benign effect. BS3 requires functional studies showing no damaging effect on the gene or gene product. Details ▾Hide ▴
Evidence considered
- PMID:21179087: L265P constitutively activates NF-kappaB and promotes survival — damaging effect.
- PMID:23836557: L265P activates BTK/NF-kappaB signaling — damaging effect.
Sources
BP1 MYD88-related disease (Waldenstrom macroglobulinemia, DLBCL) is driven by gain-of-function missense variants, not truncating loss-of-function variants. BP1 applies to genes where primarily truncating variants cause disease, which is not the case for MYD88. Details ▾Hide ▴
Evidence considered
- MYD88 disease mechanism is gain-of-function via missense variants
- not loss-of-function via truncation.
BP2 No evidence of this variant being observed in trans with a pathogenic variant (for a dominant disorder) or in cis with a pathogenic variant (any inheritance pattern). No such observations are reported in the literature or ClinVar. Details ▾Hide ▴
Evidence considered
- No evidence of trans or cis configuration with another pathogenic variant.
BP4 Multiple lines of in silico computational evidence do NOT support a benign interpretation. REVEL score of 0.735 predicts a deleterious effect. BayesDel score of 0.13148 is borderline but does not strongly predict benign impact. SpliceAI delta of 0.0 indicates no splicing impact. The weight of computational evidence favors a deleterious interpretation, not a benign one. Details ▾Hide ▴
Evidence considered
- REVEL: 0.735 (deleterious prediction
- contradicts benign interpretation).
- BayesDel: 0.13148 (borderline
- does not strongly support benign).
- SpliceAI: 0.0 (no splicing impact
- but does not address protein-level effect).
Sources
BP5 No alternative molecular basis for disease has been identified in cases harboring this variant. MYD88 L273P (L265P) is itself the primary molecular driver in Waldenstrom macroglobulinemia. BP5 is not supported. Details ▾Hide ▴
Evidence considered
- No alternative causative variant identified in cases with this MYD88 variant.
BP6 No reputable source classifies this variant as benign. The only criteria-provided ClinVar submission (Labcorp) classifies it as Uncertain Significance. BP6 is not met. Details ▾Hide ▴
PS5 No different pathogenic missense variant at codon 273 has been identified. The variant p.Leu273Pro is itself the established pathogenic change at this residue; PS5 requires a novel missense change at a residue where a different missense change is known to be pathogenic. Details ▾Hide ▴
Evidence considered
- No alternate missense at codon 273 with established pathogenicity identified. p.L273P is the known pathogenic variant.
Not assessed · 2 · no assessment recorded
PP2 Insufficient data available on MYD88 missense constraint metrics (e.g., gnomAD missense Z-score, OE ratio) to evaluate whether the gene has a low rate of benign missense variation. PP2 requires a demonstrated low rate of benign missense variation in the gene. Details ▾Hide ▴
Evidence considered
- No missense constraint data retrieved for MYD88.
Still missing
- Missense constraint metrics (Z-score
- pLI
- missense OE) not available for MYD88.
PP4 No patient-specific phenotype or family history was provided for this case. PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology. Details ▾Hide ▴
Evidence considered
- No patient phenotype available for assessment.
Still missing
- Patient phenotype not provided in case materials.
Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant (c.818T>C, p.Leu273Pro), not a null variant (nonsense, frameshift, canonical splice). The variant bucket is 'other' per the generic PVS1 framework, and PVS1 does not apply to missense variants. Details ▾Hide ▴
Evidence considered
- Variant is missense p.Leu273Pro
- null-variant criteria not met.
Sources
PS1 N/ANo alternate nucleotide change at codon 273 producing the same amino acid change (p.Leu273Pro) with established pathogenicity has been identified. This variant is itself the established pathogenic change; PS1 requires a different nucleotide substitution yielding the same amino acid alteration. Details ▾Hide ▴
Evidence considered
- No alternate nucleotide change producing p.Leu273Pro with prior pathogenic classification identified.
PM3 N/ASkipped per directive: PM3 applies to recessive disorders (detected in trans with a pathogenic variant). MYD88-related disease is dominant/somatic, not recessive. Details ▾Hide ▴
No further detail was recorded.
PM4 N/ASkipped per directive: PM4 applies to protein-length changes from non-frameshift indels or stop-loss variants, not applicable to this missense substitution. Details ▾Hide ▴
No further detail was recorded.
PM5 N/AUnable to confirm classic same-residue PM5 semantics. The variant is p.Leu273Pro, and no different pathogenic missense change at codon 273 has been identified with sufficient confidence to serve as a PM5 comparator. Per automated PM5 candidate assessment, the recommendation is not_applicable. Details ▾Hide ▴
Evidence considered
- No qualifying PM5 comparator variant at codon 273 identified.
Sources
pm5_candidates
BS4 N/ANo familial segregation data are available. MYD88 c.818T>C is a somatic mutation; BS4 (lack of segregation in affected family members) is not applicable in the absence of a familial disease model. Details ▾Hide ▴
Evidence considered
- No familial segregation data available. Disease is sporadic/somatic.
BP3 N/ASkipped per directive: BP3 applies to in-frame indels in non-repeat regions, not relevant for this substitution variant. Details ▾Hide ▴
No further detail was recorded.
BP7 N/AThis is a missense variant (c.818T>C, p.Leu273Pro), not a synonymous (silent) variant. BP7 applies exclusively to synonymous variants with no predicted splicing impact. Details ▾Hide ▴
Evidence considered
- Variant is missense
- not synonymous
- BP7 not applicable.
Identifiers
- Gene
- MYD88
- Transcript
- NM_001172567.1
- Coding (HGVS c.)
- NM_001172567.1:c.818T>C
- Protein (HGVS p.)
- NP_001166038.1:p.(Leu273Pro)
- GRCh38
- chr3:38141150 T>C
- GRCh37
- chr3:38182641 T>C
- ClinVar
- 37055
- COSMIC
- COSV57169334
Gene diagram
Every interpreted variant in MYD88, mapped onto the exon structure of NM_001172567.1. Select a row to find it on the plot.
MYD88NM_001172567.1
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in MYD88
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
42 / 1,614,060 alleles
AF 2.6e-05 · 0 homozygotes · FAF 2.07e-05
gnomAD v2.1
13 / 251,436 alleles
AF 5.17e-05 · 0 homozygotes · FAF 3.42e-05
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 2.6e-05 · 42 / 1,614,060 alleles · 0 hom · FAF 2.1e-05
| Ashkenazi Jewish3 / 29,600 | 0.0001 |
| Admixed American2 / 60,016 | 3.3e-05 |
| European (non-Finnish)34 / 1,179,918 | 2.9e-05 |
| East Asian1 / 44,870 | 2.2e-05 |
| Remaining individuals1 / 62,508 | 1.6e-05 |
| South Asian1 / 91,084 | 1.1e-05 |
0 alternate alleles recorded in 4 other groups: European (Finnish), Amish, Middle Eastern, African/African American.
gnomAD v2.1
AF 5.2e-05 · 13 / 251,436 alleles · 0 hom · FAF 3.4e-05
| Ashkenazi Jewish4 / 10,070 | 0.0004 |
| European (non-Finnish)8 / 113,740 | 7e-05 |
| Admixed American1 / 34,584 | 2.9e-05 |
0 alternate alleles recorded in 5 other groups: African/African American, East Asian, European (Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 2.60213e-05; MAF= 0.00260%, 42/1614060 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.000101351; MAF= 0.01014%, 3/29600 alleles, homozygotes = 0); grpmax FAF= 2.074e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 5.1703e-05; MAF= 0.00517%, 13/251436 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.000397219; MAF= 0.03972%, 4/10070 alleles, homozygotes = 0); grpmax FAF= 3.419e-05.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.735
- BayesDel
- 0.131
How the predictions were used
PP3 SupportingMultiple lines of in silico computational evidence support a deleterious effect. REVEL score is 0.735 (above the 0.5 threshold for pathogenicity). BayesDel score is 0.13148 (borderline/low). SpliceAI predicts no splicing impact (max delta = 0.0). The REVEL score provides supporting evidence for pathogenicity, though BayesDel is not strongly corroborative. Details ▾Hide ▴
Evidence considered
- REVEL: 0.735 (deleterious
- >0.5 threshold).
- BayesDel: 0.13148 (borderline
- below typical damaging threshold of ~0.27).
- SpliceAI: max delta = 0.0 (no splicing impact predicted).
Still missing
- BayesDel score is borderline/low and does not independently support PP3
- weight is placed primarily on REVEL.
Sources
BP4 Multiple lines of in silico computational evidence do NOT support a benign interpretation. REVEL score of 0.735 predicts a deleterious effect. BayesDel score of 0.13148 is borderline but does not strongly predict benign impact. SpliceAI delta of 0.0 indicates no splicing impact. The weight of computational evidence favors a deleterious interpretation, not a benign one. Details ▾Hide ▴
Evidence considered
- REVEL: 0.735 (deleterious prediction
- contradicts benign interpretation).
- BayesDel: 0.13148 (borderline
- does not strongly support benign).
- SpliceAI: 0.0 (no splicing impact
- but does not address protein-level effect).
Sources
BP7 N/AThis is a missense variant (c.818T>C, p.Leu273Pro), not a synonymous (silent) variant. BP7 applies exclusively to synonymous variants with no predicted splicing impact. Details ▾Hide ▴
Evidence considered
- Variant is missense
- not synonymous
- BP7 not applicable.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.735. BayesDel score = 0.13148.
10 paper records listed. 5 cited in the classification.
Cited in the classification
-
PMID 21179087 ↗Oncogenically active MYD88 mutations in human lymphoma.Ngo VN et al. · 2011 Feb 3MYD88 L265P (Leu273Pro) was identified as a recurrent somatic mutation in activated B-cell-like diffuse large B-cell lymphoma (ABC DLBCL), constitutively activating NF-kappaB and JAK/STAT signaling. Knockdown of MYD88 selectively killed L265P-mutant ABC DLBCL cell lines but not wild-type cells.→ PS3 Names this variant
-
PMID 22931316 ↗MYD88 L265P somatic mutation in Waldenström's macroglobulinemia.Treon SP et al. · 2012 Aug 30MYD88 L265P was detected in over 90% of Waldenstrom macroglobulinemia (WM) cases by whole-genome sequencing of lymphoplasmacytic cells from 30 patients. NF-kappaB activation was confirmed in primary WM cells harboring the mutation.→ PS3 → PS4 Names this variant
-
PMID 23215570 ↗MYD88 L265P somatic mutation in IgM MGUS.Landgren O et al. · 2012 Dec 6MYD88 L265P was identified in IgM-MGUS and shown to localize to the TIR domain BB-loop, a critical functional motif for MYD88 signal transduction and a known mutational hotspot in hematologic malignancies.→ PS4 → PM1 Names this variant
-
PMID 23355535 ↗Prevalence and clinical significance of the MYD88 (L265P) somatic mutation in Waldenstrom's macroglobulinemia and related lymphoid neoplasms.Varettoni M et al. · 2013 Mar 28MYD88 L265P was detected in 96% of Waldenstrom macroglobulinemia cases and 54% of IgM monoclonal gammopathy of undetermined significance (IgM-MGUS) cases by allele-specific PCR, establishing L265P as a highly prevalent and early mutational event in WM pathogenesis.→ PS4 Names this variant
-
PMID 23836557 ↗A mutation in MYD88 (L265P) supports the survival of lymphoplasmacytic cells by activation of Bruton tyrosine kinase in Waldenström macroglobulinemia.Yang G et al. · 2013 Aug 15MYD88 L265P activated BTK and NF-kappaB signaling in lymphoplasmacytic cells. Pharmacologic inhibition of BTK with ibrutinib selectively reduced survival of L265P-expressing cells, indicating dependence on the MYD88-BTK signaling axis.→ PS3 Names this variant
Other recorded publications
-
PMID 35101336 ↗Standards for the classification of pathogenicity of somatic variants in cancer (oncogenicity): Joint recommendations of Clinical Genome Resource (ClinGen), Cancer Genomics Consortium (CGC), and Variant Interpretation for Cancer Consortium (VICC).Horak P et al. · 2022No paper-specific finding is recorded.
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PMID 22918138 ↗Opportunities and challenges associated with clinical diagnostic genome sequencing: a report of the Association for Molecular Pathology.Schrijver I et al. · 2012No paper-specific finding is recorded.
-
PMID 34131312 ↗Chromosomal microarray analysis, including constitutional and neoplastic disease applications, 2021 revision: a technical standard of the American College of Medical Genetics and Genomics (ACMG).Shao L et al. · 2021No paper-specific finding is recorded.
-
PMID 23619274 ↗American College of Medical Genetics and Genomics technical standards and guidelines: microarray analysis for chromosome abnormalities in neoplastic disorders.Cooley LD et al. · 2013No paper-specific finding is recorded.
-
PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Nykamp K et al. · 2017No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
42 / 1,614,060 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
1 Uncertain significance · 1 Likely pathogenic
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/37055/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/3-38182641-T-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr3-38141150-T-C?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/3-38141150-T-C
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001172567.1%3Ac.8…
- OncoKB ↗www.oncokb.org/gene/MYD88/L273P
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=156482303
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 2.60213e-05; MAF= 0.00260%, 42/1614060 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.000101351; MAF= 0.01014%, 3/29600 alleles, homozygotes = 0); grpmax FAF= 2.074e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 5.1703e-05; MAF= 0.00517%, 13/251436 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.000397219; MAF= 0.03972%, 4/10070 alleles, homozygotes = 0); grpmax FAF= 3.419e-05.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
ClinVar
Error retrieving ClinVar entry.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.735. BayesDel score = 0.13148.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. MYD88, an adaptor protein, is frequently altered in hematologic malignancies including Waldenström's macroglobulinemia.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV57169334, n = 2493 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.