Variant classification summary

NM_000465.4:c.354T>C

BARD1 · NP_000456.2:p.(Asn118=) · NM_000465.4

GRCh37: chr2:215657031 A>G · GRCh38: chr2:214792307 A>G

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.(Asn118=)

gnomAD AF

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (supporting): absent from gnomAD v2.1 and v4.1 and both non-cancer subsets, with API verification, so the allele frequency is effectively 0.

2

BP4 (supporting): SpliceAI maximum delta score 0.009 for this synonymous variant is at or below the <=0.1 no-splice-impact cutoff.

3

PP3 not met: the same SpliceAI score of 0.009 is far below the >=0.2 supporting cutoff for a predicted splice effect.

4

PVS1, PS1, PM1, PM4, PM5, PP2, BP1 not applicable: a synonymous p.(Asn118=) change satisfies none of their structural prerequisites.

5

PS4 and PP4 not met: no affected carrier, cohort enrichment or proband phenotype is reported for this variant.

6

PP5 and BP6 not met: ClinVar variation 3260425 has zero expert-panel (3-star) submissions, only two single-laboratory classifications.

7

BA1, BS1 and BS2 not met: zero observed alleles and no heterozygous or homozygous carriers in gnomAD, so no frequency-based benign argument is available.

8

No VCEP/CSPEC or local BARD1 framework exists, so generic ACMG/AMP 2015 combination rules were applied.

Final determination: Under the generic ACMG/AMP 2015 combination rules, one supporting pathogenic criterion (PM2) combined with one supporting benign criterion (BP4) is conflicting evidence that satisfies no Pathogenic, Likely Pathogenic, Benign or Likely Benign rule, 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	PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_000465.4:c.354T>C in BARD1 is a synonymous (silent) substitution predicted to produce NP_000456.2:p.(Asn118=). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
PS1	N/A	PS1 (Richards et al. 2015, PMID:25741868) requires the same amino acid change as a previously established pathogenic variant, evaluated regardless of the underlying nucleotide change. NM_000465.4:c.354T>C in BARD1 is a synonymous (silent) substitution predicted to produce NP_000456.2:p.(Asn118=). As a result, no altered amino acid exists at this position to compare against any previously established pathogenic missense variant, so PS1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no proband or parental testing exists, so the confirmed de novo status PS2 requires cannot be established.
PS3	Not assessed	Not assessed: no functional assay data exist for BARD1 c.354T>C, and PS3 requires experimental evidence of a damaging effect.	generic_acmg_combination_rules clinvar PMID:15604628 PMID:31429903
PS4	Not met	Not met: zero affected carriers or case-control data reported for BARD1 c.354T>C, so no enrichment statistic exists to support PS4.	clinvar
PM1	N/A	PM1 (Richards et al. 2015, PMID:25741868) applies to a missense variant located in a mutational hot spot and/or a critical, well-established functional domain without benign variation. NM_000465.4:c.354T>C in BARD1 is a synonymous (silent) substitution predicted to produce NP_000456.2:p.(Asn118=). As a result, no altered residue exists to evaluate for mutational hot-spot or critical-domain membership, so PM1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
PM2	Met	Met (supporting): absent from gnomAD v2.1 and v4.1, satisfying the <=0.0001 PM2 frequency threshold, though this is a synonymous change.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	Not assessed	Not assessed: no affected-proband genotype, second BARD1 pathogenic allele, or phase evidence exists to meet the PM3 in-trans requirement.	clinvar
PM4	N/A	PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_000465.4:c.354T>C in BARD1 is a synonymous (silent) substitution predicted to produce NP_000456.2:p.(Asn118=). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	PM5 (Richards et al. 2015, PMID:25741868) requires a novel missense change at an amino acid residue where a different missense change has previously been determined to be pathogenic. NM_000465.4:c.354T>C in BARD1 is a synonymous (silent) substitution predicted to produce NP_000456.2:p.(Asn118=). As a result, no missense change exists at this residue to compare against a different pathogenic missense change at the same position, so PM5's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no proband or parental genotype data exists, so an assumed de novo occurrence for PM6 cannot be evaluated.
PP1	Not assessed	Not assessed: no pedigree or family genotyping data exists, so co-segregation for PP1 cannot be evaluated.
PP2	N/A	PP2 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene with a low rate of benign missense variation, where missense variants are a common mechanism of disease. NM_000465.4:c.354T>C in BARD1 is a synonymous (silent) substitution predicted to produce NP_000456.2:p.(Asn118=). As a result, the gene's missense-constraint properties are irrelevant because no missense change is present to evaluate, so PP2's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
PP3	Not met	Not met: SpliceAI max delta 0.009 is far below the >=0.2 PP3 supporting cutoff for this synonymous variant, which is scored on the splice path only.	spliceai generic_acmg_combination_rules
PP4	Not met	Not met: no proband or family phenotype is documented for BARD1 c.354T>C, so phenotype specificity for a single-gene disease cannot be established.	clinvar
PP5	Not met	Not met: ClinVar has zero expert-panel (3-star) classifications of this variant, only two single-laboratory submissions (Ambry Likely benign, Myriad Benign).	clinvar
BA1	Not met	Not met: absent from gnomAD v2.1 and v4.1 (frequency effectively 0), far below the >=0.05 BA1 stand-alone benign threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Not met: absent from gnomAD v2.1/v4.1, giving an allele frequency of ~0 versus the >=0.01 BS1 strong-benign threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	Not met: no carriers of any genotype in gnomAD v2.1/v4.1, so no healthy-adult observation exists to support BS2.	gnomad_v2 gnomad_v4 gnomad_canada
BS3	Not assessed	Not assessed: no functional assay exists for BARD1 c.354T>C, and BS3 requires experimental evidence of no damaging effect.	generic_acmg_combination_rules clinvar PMID:15604628 PMID:31429903
BS4	Not assessed	Not assessed: no family segregation data exists, so non-segregation with disease for BS4 cannot be demonstrated.
BP1	N/A	BP1 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene for which primarily truncating variants are known to cause disease. NM_000465.4:c.354T>C in BARD1 is a synonymous (silent) substitution predicted to produce NP_000456.2:p.(Asn118=). As a result, the gene's truncating-variant mechanism is irrelevant because no missense change is present to evaluate, so BP1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no cis/trans phase or co-occurring pathogenic BARD1 allele is documented, and no proband-level genotype exists to evaluate BP2.	clinvar
BP3	N/A	BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_000465.4:c.354T>C in BARD1 is a synonymous (silent) substitution predicted to produce NP_000456.2:p.(Asn118=). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met at supporting strength: SpliceAI max delta 0.009 is at or below the <=0.1 no-splice-impact BP4 cutoff, counted once and not reused for BP7.	spliceai generic_acmg_combination_rules
BP5	Not assessed	Not assessed: no affected case carrying BARD1 c.354T>C is documented, so an alternate molecular cause for disease cannot be evaluated.
BP6	Not met	Not met: no expert-panel (3-star) Benign/Likely benign classification exists; the 2-star ClinVar label comes only from two single clinical laboratories.	clinvar
BP7	Not met	Not met: this synonymous variant's only supporting result, SpliceAI max delta 0.009, is already counted under BP4, and no conservation data is available.	spliceai 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.