Variant classification summary

NM_001172567.1:c.818T>C

MYD88 · NP_001166038.1:p.(Leu273Pro) · NM_001172567.1

GRCh37: chr3:38182641 T>C · GRCh38: chr3:38141150 T>C

Gene: MYD88 Transcript: NM_001172567.1

Final call

Pathogenic

PS3 strong PS4 strong PM1 moderate PM2 supporting PP3 supporting

Variant details

Gene

MYD88

Transcript

NM_001172567.1

Protein

NP_001166038.1:p.(Leu273Pro)

gnomAD AF

2.6021337496747333e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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).

2

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).

3

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).

4

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).

5

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).

6

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.

7

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).

8

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.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Pathogenic classification based on the observed combination of very strong, strong, moderate, and supporting pathogenic criteria.

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	This 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.	pvs1_generic_framework
PS1	N/A	No 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.
PS2	Not met	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.
PS3	Met	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.	PMID:21179087 PMID:23836557 PMID:22931316
PS4	Met	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.	PMID:22931316 PMID:23355535 PMID:23215570 gnomad_v2 gnomad_v4
PS5	Not met	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.
PM1	Met	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.	PMID:23215570
PM2	Met	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.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	Unable 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.	pm5_candidates
PM6	Not met	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.
PP1	Not met	No cosegregation data available. MYD88-related malignancies (Waldenstrom macroglobulinemia, DLBCL) are sporadic somatic diseases; familial cosegregation studies are not applicable to a somatic mutation.
PP2	Not assessed	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.
PP3	Met	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.	revel bayesdel spliceai
PP4	Not assessed	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.
PP5	Not met	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.	clinvar
BA1	Not met	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.	gnomad_v2 gnomad_v4
BS1	Not met	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.	gnomad_v2 gnomad_v4
BS2	Not met	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.	gnomad_v2 gnomad_v4
BS3	Not met	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.	PMID:21179087 PMID:23836557
BS4	N/A	No 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.
BP1	Not met	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.
BP2	Not met	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.
BP4	Not met	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.	revel bayesdel spliceai
BP5	Not met	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.
BP6	Not met	No reputable source classifies this variant as benign. The only criteria-provided ClinVar submission (Labcorp) classifies it as Uncertain Significance. BP6 is not met.	clinvar
BP7	N/A	This 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.
BP3	N/A	Skipped per directive: BP3 applies to in-frame indels in non-repeat regions, not relevant for this substitution variant.
PM3	N/A	Skipped per directive: PM3 applies to recessive disorders (detected in trans with a pathogenic variant). MYD88-related disease is dominant/somatic, not recessive.
PM4	N/A	Skipped per directive: PM4 applies to protein-length changes from non-frameshift indels or stop-loss variants, not applicable to this missense substitution.

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