Variant classification summary

NM_000465.4:c.842C>T

BARD1 · NP_000456.2:p.(Pro281Leu) · NM_000465.4

GRCh37: chr2:215645756 G>A · GRCh38: chr2:214781032 G>A

Gene: BARD1 Transcript: NM_000465.4

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

BARD1

Transcript

NM_000465.4

Protein

NP_000456.2:p.(Pro281Leu)

gnomAD AF

3.351493462725807e-05 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 supporting: gnomAD v4.1 allele frequency is 3.35149e-05, below 0.0001.

2

BP4 supporting: missense REVEL 0.066 meets the threshold of 0.29 or lower.

Final determination: Under generic ACMG/AMP 2015 rules, one supporting pathogenic criterion and one supporting benign criterion satisfy neither a pathogenic nor a benign rule; therefore 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: the reported BARD1 p.Pro281Leu comparator was classified as a VUS, not a previously established pathogenic variant.	PMID:32959997 PMID:25741868
PS2	Not assessed	Not assessed: no exact-variant proband record with confirmed maternity, confirmed paternity, and absent family history is available.
PS3	Not assessed	Not assessed: no variant-specific validated functional assay was identified for BARD1 c.842C>T (p.Pro281Leu).	PMID:32959997 PMID:32994724 PMID:25741868 PMID:26467025
PS4	Not assessed	Not assessed: no exact-variant affected-versus-control counts or case-control OR/95% CI were available for c.842C>T.	PMID:32959997 PMID:32994724 PMID:25085752 PMID:25394175
PM1	Not assessed	Not assessed: no BARD1 domain table or qualifying hotspot evidence establishes that residue Pro281 lies in a critical functional region.	PMID:25741868
PM2	Met	Met at supporting strength: gnomAD v4.1 all-comers AF=3.35149e-05, below the PM2 threshold of <= 0.0001.	gnomad_v2 gnomad_v4 PMID:25741868
PM3	Not assessed	Not assessed: no inheritance mode or parental phase data identifies c.842C>T in trans with a pathogenic variant.	clinvar
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 pathogenic alternate missense change at Pro281 was documented, but the available same-residue search was explicitly incomplete.	pm5_candidates PMID:25741868
PM6	Not assessed	Not assessed: no exact-variant proband record documents an assumed de novo occurrence without confirmed maternity and paternity.
PP1	Not assessed	Not assessed: zero informative affected-relative co-segregations or meioses are documented for the exact c.842C>T variant.
PP2	Not assessed	Not assessed: no gene-level evidence demonstrates both low benign missense variation and a common missense disease mechanism for BARD1.	gnomad_v4 PMID:25741868
PP3	Not met	Not met: missense REVEL 0.066 is below the generic PP3 supporting threshold of 0.644.	revel
PP4	Not assessed	Not assessed: no highly specific patient phenotype or family history linking the exact variant to a single-gene BARD1 disorder was available.	PMID:32959997 PMID:32994724
PP5	Not met	Not met: ClinVar has zero expert-panel submissions and no exact-variant pathogenic or likely pathogenic expert-panel classification.	clinvar
BA1	Not met	Not met: the highest observed allele frequency is 0.000695578, below the BA1 stand-alone threshold of >= 0.05.	gnomad_v2 gnomad_v4 PMID:25741868
BS1	Not met	Not met: the highest observed allele frequency is 0.000695578, below the generic BS1 default threshold of >= 0.01.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: gnomAD reports zero homozygotes but does not document a specific healthy adult carrier or the required full early-age penetrance.	gnomad_v2 gnomad_v4 PMID:25741868
BS3	Not assessed	Not assessed: no variant-specific validated functional assay was identified showing that BARD1 c.842C>T (p.Pro281Leu) has no damaging effect.	PMID:32959997 PMID:32994724 PMID:25741868 PMID:26467025
BS4	Not assessed	Not assessed: no informative affected family member is documented as genotype-negative for the exact c.842C>T variant.
BP1	Not assessed	Not assessed: the available evidence does not establish that BARD1 disease is caused primarily by truncating variants.	PMID:25741868
BP2	Not assessed	Not assessed: no documented pathogenic partner with confirmed cis or trans phase is available for c.842C>T.	clinvar
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	Met	Met at supporting strength: missense REVEL 0.066 meets the generic BP4 threshold of <=0.29.	revel
BP5	Not assessed	Not assessed: no exact-variant case was documented with an alternate molecular basis for the reported disease.
BP6	Not met	Not met: ClinVar’s Likely benign assertions are non-expert submissions, with zero exact-variant expert-panel classifications.	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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