NM_000061.3:c.1442G>C

BTK · NP_000052.1:p.(Cys481Ser) · NM_000061.3

GRCh37: chrX:100611164 C>G · GRCh38: chrX:101356176 C>G

Gene: BTK Transcript: NM_000061.3

Final call

VUS

PS3 strong PM2 supporting

Variant details

Gene

BTK

Transcript

NM_000061.3

Protein

NP_000052.1:p.(Cys481Ser)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

PS3 strong: functional assays showed abnormal ibrutinib binding and reactivated signaling for Cys481Ser.

PM2 supporting: the exact variant was absent from gnomAD v2.1 and v4.1.

Final determination: Under generic ACMG/AMP 2015 fallback rules, PS3 strong plus PM2 supporting does not satisfy any pathogenic, likely pathogenic, benign, or likely benign combination, so the call is 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 met	Not met: reviewed reports describe C481S from the queried c.1442G>C allele, with no documented pathogenic Cys481Ser allele caused by a different nucleotide change.	PMID:25189416 PMID:24869598 PMID:27199251
PS2	Not assessed	Not assessed: no documented proband, family-history, or confirmed maternity-and-paternity evidence establishes a germline de novo occurrence.
PS3	Met	Met, strong: independent biochemical and cellular assays showed reversible ibrutinib binding, reduced BTK inhibition, and reactivated signaling for the exact Cys481Ser variant.	PMID:24869598 PMID:25189416 PMID:25082755 PMID:27282255
PS4	Not met	Not met: available reports describe BTK C481S in treatment-resistance cohorts but provide no affected-versus-control OR/RR >5.0 with a confidence interval excluding 1.0.	PMID:24869598 PMID:27199251
PM1	Not assessed	Not assessed: Cys481 is in the BTK kinase domain, but domain-wide absence of benign variation is not established by the available evidence.	PMID:27282255 gnomad_v2 gnomad_v4
PM2	Met	Met at supporting: the exact variant is absent from gnomAD v2.1 and v4.1, giving observed frequency 0 versus the <=0.0001 PM2 threshold.	gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no affected-proband germline observation or parental/offspring testing establishes this variant in trans with a pathogenic allele.
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 met	Not met: C481T and C481F/R/Y were reported as acquired resistance substitutions, but no alternate Cys481 missense variant was established as pathogenic under this rule.	PMID:27282255 PMID:26182309
PM6	Not assessed	Not assessed: no affected patient with an assumed germline de novo variant and absent parental confirmation is documented.
PP1	Not assessed	Not assessed: no affected relatives, informative meioses, or genotype-phenotype co-segregation data are reported.
PP2	Not assessed	Not assessed: no gene-wide data establish both low benign BTK missense variation and missense variants as a common disease mechanism.
PP3	Not met	Not met: this missense variant requires REVEL, but no REVEL score is available; SpliceAI and uncalibrated BayesDel cannot substitute.
PP4	Not assessed	Not assessed: no patient phenotype or family history is provided to determine whether the presentation is highly specific for a single-gene disease.
PP5	Not met	Not met: exact-variant ClinVar has 0 expert-panel submissions, so ordinary laboratory Pathogenic assertions cannot qualify for PP5.	clinvar
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, rather than reaching the >=0.05 stand-alone frequency threshold.	gnomad_v2 gnomad_v4 clinvar
BS1	Not met	Not met: no gnomAD allele frequency or grpmax FAF is reported because the variant is absent from v2.1 and v4.1.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no qualifying healthy adult hemizygous observation with documented early-age full penetrance is available.	gnomad_v2 gnomad_v4 clinvar
BS3	Not met	Not met: retained basal catalysis is outweighed by demonstrated loss of irreversible ibrutinib binding and abnormal downstream signaling for Cys481Ser.	PMID:27282255 PMID:24869598 PMID:25189416
BS4	Not assessed	Not assessed: no affected relatives with documented negative variant testing are available to demonstrate lack of segregation.
BP1	Not assessed	Not assessed: the available evidence does not show that BTK disease is caused primarily by truncating variants.
BP2	Not assessed	Not assessed: no germline observation establishes the variant in trans for a fully penetrant dominant disorder or in cis with a pathogenic allele.
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: this missense variant requires REVEL, but no REVEL score is available; SpliceAI 0.004 cannot substitute for the required predictor path.
BP5	Not assessed	Not assessed: no disease case is documented with this variant plus a confirmed alternate molecular basis for that disease.	PMID:24869598 PMID:27199251
BP6	Not met	Not met: exact-variant ClinVar has 0 expert-panel submissions and no eligible benign or likely benign expert-panel assertion for BP6.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a missense variant.	generic_acmg_combination_rules

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.