Variant classification summary

NM_000465.4:c.496C>T

BARD1 · NP_000456.2:p.(Gln166Ter) · NM_000465.4

GRCh37: chr2:215646102 G>A · GRCh38: chr2:214781378 G>A

Gene: BARD1 Transcript: NM_000465.4

Final call

Likely Pathogenic

PVS1 very strong PM2 supporting

Variant details

Gene

BARD1

Transcript

NM_000465.4

Protein

NP_000456.2:p.(Gln166Ter)

gnomAD AF

1.2394660875881105e-06 (v4.1)

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Likely Pathogenic: PVS1 very strong supports loss of function from the early BARD1 truncation.

2

Likely Pathogenic: PM2 supporting reflects an extremely rare gnomAD v4.1 allele frequency with zero homozygotes.

Final determination: Generic ACMG/AMP 2015 fallback rules classify one very strong pathogenic criterion plus one supporting criterion as Likely Pathogenic.

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	Met	Met at very strong: the nonsense variant truncates BARD1 at p.Gln166 of 778 residues within an internal coding exon, supporting loss of function without a named downgrade.	pvs1_variant_assessment pvs1_gene_context pvs1_generic_framework PMID:25741868
PS1	N/A	Not applicable: PS1 requires a missense variant, and this is a nonsense variant.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no documented maternity and paternity confirmation, parental negative testing, or disease-consistent absence of family history is available for this variant.
PS3	Not assessed	Not assessed: no reviewed study performed a validated functional assay on BARD1 c.496C>T (p.Gln166Ter), so damaging functional evidence cannot be calibrated for PS3.	PMID:20077502 PMID:21344236 PMID:25741868
PS4	Not met	Not met: aggregated BARD1 risk ratio 1.28 is below the >5.0 threshold, and its 95% CI 0.55–2.51 includes 1.0.	PMID:28888541
PM1	N/A	Not applicable: PM1 requires a missense variant, and this is a nonsense variant.	generic_acmg_combination_rules
PM2	Met	Met at supporting strength: gnomAD v4.1 AF is 1.23947e-06 with zero homozygotes, below the PM2 threshold of <= 0.0001.	gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: BARD1-related cancer predisposition is not documented here as a recessive disorder, and no recessive trans-observation is provided.
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a nonsense variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	Not applicable: PM5 requires a missense variant, and this is a nonsense variant.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no assumed de novo occurrence, negative parental testing, or family history consistent with de novo inheritance is documented for this variant.
PP1	Not assessed	Not assessed: zero variant-specific affected-relative genotypes, unaffected-relative genotypes, or informative meioses are documented for cosegregation.
PP2	N/A	Not applicable: PP2 requires a missense variant, and this is a nonsense variant.	generic_acmg_combination_rules
PP3	N/A	Not applicable: the variant is a nonsense change, p.(Gln166Ter), outside the generic PP3 scope for missense or splice-region/intronic variants.
PP4	Not assessed	Not assessed: no case-specific phenotype or family-history evidence is available to establish a highly specific single-etiology disease presentation.
PP5	Not met	Not met: the exact ClinVar variant has Pathogenic laboratory submissions but zero expert-panel submissions required for PP5.	clinvar
BA1	Not met	Not met: gnomAD v4.1 allele frequency is 1.23947e-06, far below the BA1 stand-alone threshold of >= 0.05.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: gnomAD v2.1 maximum subgroup frequency is 8.81135e-06, below the generic BS1 threshold of >= 0.01.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: gnomAD shows heterozygous alleles but does not document healthy adult status or full early-age penetrance for BS2.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no validated assay on BARD1 c.496C>T (p.Gln166Ter) demonstrated a normal protein function or splicing result required for BS3.	PMID:20077502 PMID:21344236 PMID:25741868
BS4	Not assessed	Not assessed: no affected family member with a documented negative genotype for NM_000465.4:c.496C>T is reported.
BP1	N/A	Not applicable: BP1 requires a missense variant, and this is a nonsense variant.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no parent/offspring or other phase data establishes the variant in trans or cis with a pathogenic variant.
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a nonsense variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	N/A	Not applicable: the variant is a nonsense change, p.(Gln166Ter), outside the generic BP4 scope for missense or splice-region/intronic variants.
BP5	Not assessed	Not assessed: the case evidence does not identify an alternate molecular basis for the patient's disease.
BP6	Not met	Not met: the exact ClinVar record has no expert-panel submission and reports Pathogenic rather than Benign or Likely benign.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a nonsense variant.	generic_acmg_combination_rules

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