The MYD88 NM_002468.5:c.755T>C (NP_002459.3:p.(Leu252Pro)) missense variant has not previously been reported in somatic cancers (COSMIC). Based on available guidelines, this variant is considered to be a Variant of Uncertain Significance (VUS).
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.MYD88 encodes an adaptor protein that helps transmit signals from Toll-like and interleukin-1 receptors, activating immune and inflammatory responses. Loss of MYD88 function can impair immune defense and increase susceptibility to bacterial infections. MYD88 acts as an oncogene and is involved in several blood cancers, including Waldenström macroglobulinemia and certain lymphomas.
The recorded framework is Generic ACMG/AMP 2015 with ClinGen SVI recommendations. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
The applied criteria and their strengths are shown as assessed under the stated framework.
Met at supporting strength: gnomAD v4.1 AF is 2.60213e-05, below the PM2 supporting threshold of 0.0001.
Met at supporting strength: missense REVEL score 0.735 exceeds the generic PP3 supporting threshold of 0.644.
No benign criterion marked as applied in the recorded assessment.
VUS: PM2 supporting plus PP3 supporting do not satisfy a generic ACMG/AMP 2015 pathogenic, benign, likely pathogenic, or likely benign combination rule.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 42 / 1,614,060 alleles. Recorded AF 2.60213e-05. Recorded homozygote count 0.
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.
This variant is present in gnomAD-Canada v1.0 (AF= 5.430650591940915e-05, 1/18414 alleles, homozygotes = 0).
Recorded REVEL score: 0.735. Refer to the recorded PP3/BP4 rationale for interpretation.
2 Uncertain significance · 1 Likely pathogenic. ClinVar API review status: criteria provided, single submitter.
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: not classified.
This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.
ACMG/AMP criteria under Generic ACMG/AMP 2015 with ClinGen SVI recommendations, with the data and sources behind each one.
28 criteria with recorded statuses: 2 met · 7 not met · 15 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
No VCEP covers MYD88, so the generic ACMG/AMP rules govern.
The exact queried variant is MYD88 NM_002468.5:c.755T>C, p.Leu252Pro; literature repeatedly identified as PS4 evidence concerns the different MYD88 L265P variant and was not transferred.
The exact-variant ClinVar record has no expert-panel submission, so non-expert pathogenic submissions do not trigger PP5 and no benign expert-panel submission triggers BP6.
Neither PM3 nor BP2 is assessed because the case lacks informative phase data and a documented second pathogenic allele in an affected individual or family.
The available MYD88 publications describe the different somatic L265P variant and do not establish allelic evidence for c.755T>C (p.Leu252Pro).
No criteria match.
No VCEP-specific population source or threshold applies, so the generic all-comers gnomAD totals were used. The variant is rare but observed in gnomAD v4.1 at AF 2.60213e-05 (42/1,614,060 alleles; 0 homozygotes), which is at or below the supplied generic PM2 supporting threshold of 0.0001; gnomAD v2.1 exomes likewise show AF 5.1703e-05 (13/251,436 alleles; 0 homozygotes). Because the variant is observed rather than absent, the supporting PM2 threshold is the applicable generic calibration.
Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium. ... PM2 (supporting): <= 0.0001 — SVI recommendation to downgrade PM2 to Supporting (ClinGen SVI 2020) (PMID:25741868)
The variant is a missense change, NP_002459.3:p.(Leu252Pro), so the applicable computational path is REVEL only; the SpliceAI result is not used for PP3/BP4 in this missense situation. REVEL is 0.735, meeting the generic ClinGen SVI supporting PP3 threshold of >= 0.644. BayesDel is not used because no generic ACMG-strength calibration is established for it.
Missense variant -> REVEL only. ... PP3 (supporting): >= 0.644 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
The authoritative vcep_materials.json domain_tables entry for MYD88 is absent because no VCEP framework is available. The reviewed literature establishes a recurrent MYD88 L265P hotspot in the TIR domain, but the case variant is L252P; it does not establish residue 252 as a mutational hotspot or a critical, well-established functional domain location without benign variation. The hotspot lookup also reported no statistically significant hotspot for MYD88 L252.
Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.
The generic ACMG/AMP PP5 rule requires a reputable source to recently report the exact variant as pathogenic when the underlying evidence is unavailable for independent evaluation. ClinVar variation 37055 has no expert-panel submission (expert_panel_submissions = 0). Its exact-variant pathogenic or likely pathogenic entries are non-expert submissions without assertion criteria: OMIM reports Pathogenic and Wasik Lab reports Likely pathogenic; other submissions report Uncertain significance or Oncogenic. These do not satisfy the required exact-variant expert-panel classification rule, so PP5 is not met.
Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.
No VCEP-specific population source or threshold applies, so the generic all-comers gnomAD totals were used. The variant is present at AF 2.60213e-05 (42/1,614,060 alleles; 0 homozygotes) in gnomAD v4.1, with the highest reported ancestry AF 0.000101351 in the Ashkenazi Jewish population; both are far below the generic BA1 stand-alone threshold of 0.05. The gnomAD v2.1 exome AF was also only 5.1703e-05 (13/251,436 alleles).
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium. ... BA1 (stand-alone): >= 0.05 — ACMG/AMP 2015 stand-alone benign allele frequency (PMID:25741868)
No VCEP-specific population source or threshold applies, so the generic all-comers gnomAD totals were used. The highest relevant frequency is 2.60213e-05 overall in gnomAD v4.1, with a maximum ancestry AF of 0.000101351 in the Ashkenazi Jewish population; these do not exceed the generic 0.01 default for an allele frequency greater than expected for the disorder. The frequency is low enough that a disorder-specific maximum-credible-allele-frequency calculation is not needed to reject the generic BS1 path; no ancestry-restricted elevation suggesting a founder or reduced-penetrance exception is present at the BS1 threshold.
Allele frequency is greater than expected for the disorder. ... BS1 (strong): >= 0.01 — Generic SVI default; per-gene derivation preferred (Whiffin et al. 2017) (PMID:28518168)
The available population data show no homozygotes for the variant in gnomAD v2.1 or v4.1 and therefore provide no observation of the variant in a healthy adult in the homozygous state. No separate healthy-adult clinical observation establishing the BS2 condition is documented. Accordingly, the criterion is not met.
Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.
The variant is a missense change, so BP4 must be assessed through the REVEL path only; SpliceAI cannot substitute for a non-supportive missense REVEL result. REVEL is 0.735, which is above the generic ClinGen SVI supporting BP4 threshold of <= 0.29, so BP4 is not met. BayesDel is not used because no generic ACMG-strength calibration is established for it.
Missense variant -> REVEL only. ... BP4 (supporting): <= 0.29 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
The generic ACMG/AMP BP6 rule requires a reputable source to recently report the exact variant as benign when the underlying evidence is unavailable for independent evaluation. ClinVar variation 37055 has no expert-panel submission and no exact-variant Benign or Likely benign classification; the recorded submissions are Uncertain significance, Oncogenic, Pathogenic, and Likely pathogenic, all non-expert/single-submitter or without assertion criteria. BP6 is therefore not met.
Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.
The variant is MYD88 p.Leu252Pro. The reviewed literature reports MYD88 p.Leu265Pro, a different amino-acid residue, and does not establish a previously pathogenic MYD88 Leu252Pro variant caused by another nucleotide change. Therefore the required same-amino-acid comparator was not identified; the criterion cannot be applied from the available evidence.
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
No proband-level evidence was identified documenting the disease phenotype, absence of family history, and confirmed maternity and paternity for NM_002468.5:c.755T>C; therefore, the defining requirements for PS2 cannot be assessed.
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
PS3 cannot be assessed for NM_002468.5:c.755T>C (p.Leu252Pro). The functional publications reviewed study the distinct MYD88 p.Leu265Pro variant, not p.Leu252Pro: PMID:21179087 reports gain-of-function signaling for L265P, PMID:22931316 reports signaling inhibition in L265P-expressing cells, PMID:23355535 describes L265P-associated signaling, and PMID:23836557 reports enhanced survival and signaling for L265P. These results cannot be transferred to the present variant, and no validated, reproducible, variant-specific assay evidence for p.Leu252Pro is available in the reviewed sources.
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
The generic ACMG/AMP PS4 rule requires significantly increased prevalence in affected individuals compared with controls, with OR/RR >5.0 and a confidence interval excluding 1.0. The literature-pass PS4 leads were checked against the extracted full-text findings. PMID:22931316, PMID:23215570, and PMID:23355535 report MYD88 L265P, not this exact variant NM_002468.5:c.755T>C (p.Leu252Pro); PMID:21179087 likewise reports L265P and does not mention L252P. PMID:22918138 and PMID:35101336 do not report this variant. Therefore no exact-variant affected-versus-control counts, case frequency, matched-ancestry control frequency, OR/RR, or 95% CI are available for this variant, so PS4 cannot be assessed. No numeric comparison is performed because the required exact-variant estimate is unavailable.
The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. ... Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0.
PM3 cannot be assessed because no parent or offspring testing establishes phase, no affected-proband compound-heterozygous observation is documented, and the available evidence does not establish a recessive MYD88 disorder context for this variant. No pathogenic variant in trans is identified.
For recessive disorders, detected in trans with a pathogenic variant
The variant is MYD88 p.Leu252Pro. The reviewed papers report the different-residue variant p.Leu265Pro, and the available PM5 candidate file contains no same-residue comparator candidates. No previously pathogenic missense change at residue 252 was established in the available evidence, so PM5 cannot be applied.
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
No proband-level evidence was identified documenting the disease phenotype, absence of family history, or an assumed de novo event without parental confirmation for NM_002468.5:c.755T>C; therefore, PM6 cannot be assessed.
Assumed de novo, but without confirmation of paternity and maternity.
No affected family members, variant-positive relatives, variant-negative relatives, meioses, or phenotype-segregation data were identified for NM_002468.5:c.755T>C; co-segregation therefore cannot be assessed.
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease. ... May be used as stronger evidence with increasing segregation data.
The available evidence does not provide a gene-level assessment demonstrating both a low rate of benign MYD88 missense variation and that missense variants are a common disease mechanism for the applicable disorder. Reports of recurrent somatic MYD88 L265P and separate literature indicating MYD88 loss of function do not establish both PP2 requirements for this variant.
Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.
The generic ACMG/AMP PP4 rule requires the patient's phenotype or family history to be highly specific for a disease with a single genetic etiology. The case evidence identifies the variant and literature context but provides no patient phenotype, family history, or disease-specific clinical presentation for this case. PP4 therefore cannot be assessed.
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
BS3 cannot be assessed for NM_002468.5:c.755T>C (p.Leu252Pro). The reviewed functional studies do not provide well-established evidence of no damaging effect for this variant; they evaluate the distinct MYD88 p.Leu265Pro substitution and report activating or survival-associated effects. No variant-specific benign functional or splicing assay with suitable controls was identified.
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
No affected family members with documented absence of NM_002468.5:c.755T>C, and no pedigree or phenotype data allowing evaluation of phenocopies or multiple pathogenic variants, were identified; lack of segregation cannot be assessed.
Lack of segregation in affected members of a family.
The available gene-context evidence indicates MYD88 loss of function has been discussed in germline disease literature, but it does not establish that primarily truncating variants are known to cause the relevant disease. The evidence also includes recurrent oncogenic missense MYD88 variation, so a primarily truncating disease mechanism cannot be concluded from the supplied materials.
Missense variant in a gene for which primarily truncating variants are known to cause disease.
BP2 cannot be assessed because no affected-proband or family observation documents NM_002468.5:c.755T>C in trans with a pathogenic variant in a fully penetrant dominant disorder or in cis with a pathogenic variant under any inheritance pattern.
Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.
The generic ACMG/AMP BP5 rule requires the variant to be found in a case with an alternate molecular basis for disease. The reviewed evidence contains no case-specific report showing this exact variant in a patient whose disease is explained by another molecular cause. Reports of MYD88 L265P are different variants and cannot establish BP5 for p.Leu252Pro. BP5 therefore cannot be assessed.
Variant found in a case with an alternate molecular basis for disease.
PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_002468.5:c.755T>C in MYD88 is a missense substitution predicted to produce NP_002459.3:p.(Leu252Pro). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PVS1 for MYD88, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_null_variant_class
PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_002468.5:c.755T>C in MYD88 is a missense substitution predicted to produce NP_002459.3:p.(Leu252Pro). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PM4 for MYD88, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel
BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_002468.5:c.755T>C in MYD88 is a missense substitution predicted to produce NP_002459.3:p.(Leu252Pro). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP3 for MYD88, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_repeat_region_indel
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_002468.5:c.755T>C in MYD88 is a missense substitution predicted to produce NP_002459.3:p.(Leu252Pro). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for MYD88, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
Every interpreted variant in MYD88, mapped onto the exon structure of NM_002468.5. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| 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 |
| Ashkenazi Jewish4 / 10,070 | 0.0004 |
| European (non-Finnish)8 / 113,740 | 7e-05 |
| Admixed American1 / 34,584 | 2.9e-05 |
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.
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.
This variant is present in gnomAD-Canada v1.0 (AF= 5.430650591940915e-05, 1/18414 alleles, homozygotes = 0).
The variant is a missense change, NP_002459.3:p.(Leu252Pro), so the applicable computational path is REVEL only; the SpliceAI result is not used for PP3/BP4 in this missense situation. REVEL is 0.735, meeting the generic ClinGen SVI supporting PP3 threshold of >= 0.644. BayesDel is not used because no generic ACMG-strength calibration is established for it.
Missense variant -> REVEL only. ... PP3 (supporting): >= 0.644 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
The variant is a missense change, so BP4 must be assessed through the REVEL path only; SpliceAI cannot substitute for a non-supportive missense REVEL result. REVEL is 0.735, which is above the generic ClinGen SVI supporting BP4 threshold of <= 0.29, so BP4 is not met. BayesDel is not used because no generic ACMG-strength calibration is established for it.
Missense variant -> REVEL only. ... BP4 (supporting): <= 0.29 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_002468.5:c.755T>C in MYD88 is a missense substitution predicted to produce NP_002459.3:p.(Leu252Pro). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for MYD88, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.735. BayesDel score = 0.13148.
9 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
The MYD88 L265P mutant nucleates a signalling complex in ABC DLBCLs that includes phosphorylated IRAK1, consistent with a gain-of-function phenotype.
Results, paragraph beginning "To assess the biochemical and functional consequences of the MYD88 mutations"; Figure 3
Myeloid differentiation factor 88 (MYD88) L265P somatic mutation is highly prevalent in Waldenström macroglobulinemia (WM) and supports malignant growth through nuclear factor κB (NF-κB). By lentiviral knockdown or use of a MYD88 inhibitor, decreased phosphorylation of the NF-κB gatekeeper IκBα and survival occurred in MYD88 L265P-expressing WM cells. Conversely, WM cells engineered to overexpress MYD88 L265P showed enhanced survival.
Abstract
This change predicted a switch of leucine to proline at amino acid position 265 (L265P).
Results, "Identification of MYD88 L265P as the Most Common Somatic Alteration," first paragraph
These studies would suggest that IgM MGUS itself is heterogeneous and that MYD88 L265P is probably a driver mutation.
Authors' reply, page 2257
The single aminoacid mutation in the MYD88 gene affects the Toll/IL-1 receptor (TIR) domain of adaptor protein MYD88, and favors tumor cell survival through IRAK1 (interleukin-1 receptor associated kinase)/IRAK4, and NF-kB (nuclear factor kappa-light-chain-enhancer of activated B cells) signaling.
Introduction, page 3; the studied variant is identified elsewhere as MYD88 (L265P) / T794C
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
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.
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.
This variant is present in gnomAD-Canada v1.0 (AF= 5.430650591940915e-05, 1/18414 alleles, homozygotes = 0).
This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories) and as Likely pathogenic (1 clinical laboratory). (ClinVarID = 37055)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.735. BayesDel score = 0.13148.
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: not classified.
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.