Variant classification summary

NM_006361.6:c.251G>A

HOXB13 · NP_006352.2:p.(Gly84Glu) · NM_006361.6

GRCh37: chr17:46805705 C>T · GRCh38: chr17:48728343 C>T

Gene: HOXB13 Transcript: NM_006361.6

Final call

VUS

PP1 supporting

Variant details

Gene

HOXB13

Transcript

NM_006361.6

Protein

NP_006352.2:p.(Gly84Glu)

gnomAD AF

0.0017336176846352402 (v4.1)

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PP1 supporting: complete co-segregation was reported in 34 families, with significant over-transmission to affected sons (P=6.5×10⁻⁶).

Final determination: Under the generic ACMG/AMP 2015 fallback, one supporting pathogenic criterion alone satisfies no Likely Pathogenic or Pathogenic rule and no benign rule, 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 assessed	Not assessed: no qualifying pathogenic HOXB13 variant with a different nucleotide change producing the same p.Gly84Glu substitution was identified.
PS2	Not assessed	Not assessed: no affected proband with confirmed maternity and paternity is documented as carrying a de novo variant.
PS3	Not assessed	Not assessed: no variant-specific functional assay was identified; reviewed studies were genetic association analyses, and the only functional paper tested wild-type HOXB13 overexpression.	PMID:15964834 PMID:23064873 PMID:24026887 PMID:22841674 PMID:26517352 oncokb
PS4	Not met	Not met: verified exact-variant studies reported ORs of 3.248-4.51, each below the generic PS4 threshold of OR >5.0.	PMID:23064873 PMID:24026887 PMID:22841674 PMID:26517352
PM1	Not assessed	Not assessed: p.Gly84Glu lies in the first MEIS-interacting domain, but critical-domain status and absence of benign variation are not established.	PMID:24026887
PM2	Not met	Not met: the variant occurs at 0.186% in gnomAD v2.1 non-cancer exomes and 0.147% in v3.1 non-cancer genomes, so it is not absent from controls.	gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: HOXB13 G84E is evaluated in a dominant susceptibility context, not the recessive disorder context required for PM3.	PMID:23064873
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 different pathogenic missense substitution at HOXB13 residue 84 was identified for comparison with p.Gly84Glu.
PM6	Not assessed	Not assessed: no affected proband is documented with an assumed de novo variant lacking parental confirmation.
PP1	Met	Met at supporting strength: complete co-segregation was reported in 34 families, with over-transmission to affected sons at P=6.5×10−6.	PMID:23064873
PP2	Not assessed	Not assessed: missense disease association is documented, but no gene-level evidence establishes a low rate of benign HOXB13 missense variation.	PMID:22841674 PMID:23064873
PP3	Not met	Not met: missense REVEL score 0.448 is below the PP3 supporting threshold of >=0.644 and lies in the gray zone.	revel
PP4	Not assessed	Not assessed: the patient's phenotype and family history are not provided, so specificity for a single genetic etiology cannot be judged.
PP5	Not met	Not met: ClinVar shows zero expert-panel submissions for the exact variant, so laboratory and aggregate pathogenic labels cannot trigger PP5.	clinvar
BA1	Not met	Not met: the highest ancestry-specific frequency is 0.769%, far below the generic BA1 threshold of 5%.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: the maximum Finnish frequency is 0.769%, below the generic 1% BS1 default, with founder and reduced-penetrance context against applying that default alone.	gnomad_v2 gnomad_v4 PMID:22841674
BS2	Not assessed	Not assessed: five gnomAD homozygotes are reported, but healthy-adult status is undocumented and HOXB13 prostate-cancer susceptibility is late-onset with 33% carrier risk by age 80.	gnomad_v2 gnomad_v4 PMID:22841674
BS3	Not assessed	Not assessed: no variant-specific functional study demonstrated preserved HOXB13 protein function or splicing; available studies were genetic association analyses.	PMID:15964834 PMID:23064873 PMID:24026887 PMID:22841674 PMID:26517352
BS4	Not assessed	Not assessed: mixed co-segregation is reported, but no specific affected non-carriers are documented to establish lack of segregation.	PMID:23064873
BP1	Not met	Not met: HOXB13 disease evidence prominently documents the missense p.Gly84Glu mechanism, not a disease mechanism primarily caused by truncating variants.	PMID:22841674 PMID:23064873
BP2	Not assessed	Not assessed: no second pathogenic variant or cis/trans phase is reported for the affected individuals carrying HOXB13 G84E.	PMID:23064873
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 0.448 exceeds the BP4 supporting threshold of <=0.29 and lies in the gray zone.	revel
BP5	Not assessed	Not assessed: no alternate molecular basis for disease is documented in the available case evidence.
BP6	Not met	Not met: ClinVar has no exact-variant expert-panel benign or likely-benign classification, so BP6 cannot be applied.	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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