NM_000465.4:c.1285G>A

BARD1 · NP_000456.2:p.(Glu429Lys) · NM_000465.4

GRCh37: chr2:215645313 C>T · GRCh38: chr2:214780589 C>T

Gene: BARD1 Transcript: NM_000465.4

Final call

VUS

Variant details

Gene

BARD1

Transcript

NM_000465.4

Protein

NP_000456.2:p.(Glu429Lys)

gnomAD AF

4.33703468264678e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

No ACMG/AMP criterion was met, so no pathogenic or benign combination threshold was satisfied; under the generic ACMG/AMP 2015 fallback this resolves to Variant of Uncertain Significance.

Final determination: Generic ACMG/AMP 2015 combination rules (PMID:25741868): with zero met criteria - no PVS1/PS/PM/PP pathogenic evidence and no BA1/BS/BP benign evidence is applied - none of the Pathogenic, Likely Pathogenic, Benign, or Likely Benign combination thresholds is satisfied, so the variant is classified as Variant of Uncertain Significance.

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: this missense change (p.Glu429Lys) does not belong to the null variant classes — nonsense, frameshift, or splice-site — that PVS1 requires.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not met	Not met: the only ClinVar classifications of p.Glu429Lys are two laboratory submissions of uncertain significance, with no pathogenic assertion for this amino acid change.	clinvar
PS2	Not assessed	Not assessed: no de novo occurrence of this variant with confirmed parentage has been reported in ClinVar or the literature.	clinvar generic_acmg_combination_rules
PS3	Not assessed	Not assessed: no variant-specific functional assay data exist for p.Glu429Lys; neither OncoKB nor either ClinVar submission reports any functional study.	oncokb clinvar generic_acmg_combination_rules
PS4	Not assessed	Not assessed: no case-control or cohort enrichment data exist for this exact variant in ClinVar or the reviewed literature.	clinvar PMID:17508274 PMID:31429903 PMID:34012068
PM1	Not met	Not met: p.Glu429Lys is not in a statistically significant cancer hotspot and has no record in COSMIC somatic data.	oncokb
PM2	Not assessed	Not assessed: insufficient population-frequency evidence was available to evaluate PM2.
PM3	N/A	Not applicable: PM3 applies only to recessive disorders with a variant in trans, and BARD1 predisposition here is a heterozygous dominant-susceptibility context.	generic_acmg_combination_rules clinvar pvs1_gene_context gnomad_v4
PM4	N/A	Not applicable: PM4 applies to protein-length changes, and this missense substitution does not alter protein length.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no alternate pathogenic missense at codon 429 was identified, but the same-residue search was incomplete, so evidence is insufficient.	clinvar pm5_candidates
PM6	Not assessed	Not assessed: no assumed de novo occurrence (parental testing without confirmed parentage) has been documented for this variant.	clinvar generic_acmg_combination_rules
PP1	Not assessed	Not assessed: no co-segregation data in affected family members were available.	clinvar generic_acmg_combination_rules
PP2	Not assessed	Not assessed: no missense-constraint metric (such as a gnomAD Z-score) or curated missense-versus-truncating distribution was available for BARD1.	pvs1_gene_context
PP3	Not met	Not met: REVEL 0.409 falls within the 0.250–0.750 gray zone, below the >0.750 PP3-supporting cutoff.	revel spliceai bayesdel generic_acmg_combination_rules
PP4	Not assessed	Not assessed: no proband-level phenotype or family history was available to show a highly specific single-etiology presentation.	clinvar
PP5	Not met	Not met: no ClinVar expert panel has classified this exact variant as pathogenic or likely pathogenic (expert-panel submissions: 0).	clinvar
BA1	Not assessed	Not assessed: insufficient population-frequency evidence was available to evaluate BA1.
BS1	Not assessed	Not assessed: insufficient population-frequency evidence was available to evaluate BS1.
BS2	Not assessed	Not assessed: no observations of this variant in unaffected individuals were available.
BS3	Not assessed	Not assessed: no functional assay data exist for p.Glu429Lys, and the absence of such data cannot itself support a benign effect.	oncokb clinvar generic_acmg_combination_rules
BS4	Not assessed	Not assessed: no family-based non-segregation observations (affected relatives lacking the variant) were available.	clinvar generic_acmg_combination_rules
BP1	Not assessed	Not assessed: available evidence does not establish that BARD1 disease is primarily caused by truncating variants, as BP1 requires.	pvs1_gene_context
BP2	Not met	Not met: this variant is never observed in trans with a pathogenic allele, and BARD1 predisposition is not a fully dominant disorder.	generic_acmg_combination_rules clinvar
BP3	N/A	Not applicable: BP3 applies to in-frame insertions or deletions in repeat regions, not to missense substitutions.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: REVEL 0.409 is above the <0.250 BP4-supporting cutoff, so the variant falls in the gray zone.	revel spliceai bayesdel generic_acmg_combination_rules
BP5	Not assessed	Not assessed: no data show an alternative molecular cause of disease in any carrier of this variant.
BP6	Not met	Not met: no ClinVar expert panel has classified this exact variant as benign or likely benign (expert-panel submissions: 0).	clinvar
BP7	N/A	Not applicable: BP7 applies only to synonymous (silent) variants, and this is a missense substitution.	generic_acmg_combination_rules

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