NM_002468.5:c.755T>C

MYD88 · NP_002459.3:p.(Leu252Pro) · NM_002468.5

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

Gene: MYD88 Transcript: NM_002468.5

Final call

VUS

PM2 supporting PP3 supporting

Variant details

Gene

MYD88

Transcript

NM_002468.5

Protein

NP_002459.3:p.(Leu252Pro)

gnomAD AF

2.6021337496747333e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

PM2 supporting: gnomAD v4.1 allele frequency is 2.60213e-05, below 0.0001.

PP3 supporting: REVEL is 0.735, above the adjudicated threshold of 0.644.

VUS: two supporting criteria do not satisfy a generic ACMG/AMP 2015 classification combination rule.

Final determination: Under the generic ACMG/AMP 2015 fallback, PM2 supporting plus PP3 supporting does not satisfy any pathogenic, likely pathogenic, benign, or likely benign rule, resulting in VUS.

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	Not applicable: PVS1 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: reviewed reports describe MYD88 p.Leu265Pro, not a previously established pathogenic change at residue 252 with the same amino-acid substitution.	PMID:21179087 PMID:22931316 PMID:23215570 PMID:23355535
PS2	Not assessed	Not assessed: no documented proband phenotype, family-history status, or confirmed maternity and paternity were available for this variant.
PS3	Not assessed	Not assessed: reviewed functional studies concern MYD88 p.Leu265Pro, whereas this variant is p.Leu252Pro, with no variant-specific validated assay evidence available.	PMID:21179087 PMID:22931316 PMID:23355535 PMID:23836557
PS4	Not assessed	Not assessed: no exact-variant affected-versus-control counts, odds ratio, relative risk, or 95% confidence interval were reported for MYD88 p.Leu252Pro.	PMID:22918138 PMID:22931316 PMID:23215570 PMID:23355535 PMID:35101336
PM1	Not met	Not met: MYD88 L252P lacks evidence of a residue-specific hotspot or critical domain location without benign variation; the documented hotspot is L265P.	PMID:21179087 PMID:23215570 PMID:23355535
PM2	Met	Met at supporting strength: gnomAD v4.1 AF is 2.60213e-05, below the PM2 supporting threshold of 0.0001.	gnomad_v4 gnomad_v2
PM3	Not assessed	Not assessed: No parent/offspring phase data or documented recessive disorder with a trans pathogenic allele are available for MYD88 c.755T>C.
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no previously pathogenic alternate missense change at MYD88 residue 252 was established, while the reported comparator p.Leu265Pro is at residue 265.	PMID:21179087 PMID:22931316 PMID:23215570 PMID:23355535 pm5_candidates
PM6	Not assessed	Not assessed: no documented proband phenotype, family-history status, or assumed de novo event without parental confirmation was available.
PP1	Not assessed	Not assessed: no affected relatives or informative variant-positive and variant-negative family meioses were documented for co-segregation.
PP2	Not assessed	Not assessed: evidence does not establish both low benign missense variation and a common missense disease mechanism for MYD88 under this criterion.	gnomad_v4
PP3	Met	Met at supporting strength: missense REVEL score 0.735 exceeds the generic PP3 supporting threshold of 0.644.	revel
PP4	Not assessed	Not assessed: the case contains no patient phenotype or family-history information establishing a highly specific single-gene disease presentation.
PP5	Not met	Not met: ClinVar has no exact-variant expert-panel classification; pathogenic entries are non-expert submissions without assertion criteria.	clinvar
BA1	Not met	Not met: gnomAD v4.1 AF is 2.60213e-05, far below the 0.05 BA1 threshold.	gnomad_v4 gnomad_v2
BS1	Not met	Not met: maximum observed gnomAD v4.1 ancestry AF is 0.000101351, below the generic 0.01 BS1 default.	gnomad_v4 gnomad_v2
BS2	Not met	Not met: gnomAD v4.1 reports 0 homozygotes among 1,614,060 alleles, with no separate healthy-adult observation.	gnomad_v4 gnomad_v2
BS3	Not assessed	Not assessed: no well-established benign assay tests MYD88 p.Leu252Pro; available studies evaluate the distinct p.Leu265Pro substitution and report activating effects.	PMID:21179087 PMID:22931316 PMID:23355535 PMID:23836557
BS4	Not assessed	Not assessed: no affected relatives with documented variant-negative results were available to evaluate lack of segregation.
BP1	Not assessed	Not assessed: MYD88 loss-of-function literature is present, but the evidence does not show that disease is caused primarily by truncating variants.
BP2	Not assessed	Not assessed: No cis or trans observation with a pathogenic variant is documented for MYD88 c.755T>C in an informative affected individual or family.
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: missense REVEL score 0.735 is above the generic BP4 supporting threshold of 0.29.	revel
BP5	Not assessed	Not assessed: no case-specific alternate molecular basis for disease was documented alongside MYD88 p.Leu252Pro.	PMID:22931316 PMID:23215570 PMID:23355535 clinvar
BP6	Not met	Not met: ClinVar has no exact-variant expert-panel benign or likely-benign classification for MYD88 p.Leu252Pro.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a missense variant.	generic_acmg_combination_rules

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