Classification rationale

BP7 VUS

BARD1 c.2127A>G

The BARD1 c.2127A>G (p.Pro709=) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar with Likely benign and Benign submissions.¹ This variant is absent from gnomAD v2.1 and gnomAD v4.1, with an observed allele frequency of 0, which is below the benign frequency thresholds and does not by itself support pathogenicity for a synonymous variant.² In silico analysis predicts no meaningful splice effect, with a SpliceAI maximum delta score of 0.00, and the variant is synonymous at p.Pro709=, supporting BP7 and not supporting PP3.³

BP7 → VUS

1 cosmicclinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 spliceai ↗prefetch

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

Gene diagram · NM_000465.4 · variants mapped to exon structure

BARD1 NM_000465.4

Fetching transcript structure from UCSC…

Applied criteria · 1 applied · 18 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 1

Strength Supporting Moderate Strong Very strong

BP7 supporting review Benign

This variant is a synonymous change, NM_000465.4:c.2127A>G (p.Pro709=), and SpliceAI predicts no significant splice impact with a maximum delta score of 0.00. Available evidence is consistent with no effect on splicing or protein sequence, so BP7 is met at supporting strength.

NP_000456.2:p.(Pro709=)SpliceAI max delta 0.00

spliceai ↗

Assessed · not applied · 6 not met · 12 not assessed

Pathogenic

PS2 No confirmed de novo occurrence with verified maternity and paternity was identified, so PS2 was not assessed.

PS3 No well-established functional studies demonstrating a damaging effect of this specific variant were identified, so PS3 was not assessed.

PS4 Available evidence does not show that this variant is enriched in affected individuals compared with controls.

PM1 This variant has not been shown to occur in a well-established critical functional domain or mutational hotspot without benign variation.

PM2 This variant is absent from gnomAD v2.1 and gnomAD v4.1, but absence from population databases alone does not establish pathogenicity for a synonymous variant; PM2 is therefore not met.

PM6 No assumed de novo occurrence without confirmed parentage was identified, so PM6 was not assessed.

PP1 No segregation data were identified for this variant, so PP1 was not assessed.

PP3 Available in silico evidence does not support a deleterious effect.

PP4 No phenotype or family history information specific enough to support a highly specific BARD1-related presentation was identified, so PP4 was not assessed.

PP5 ClinVar lists this variant as Likely benign and Benign, not pathogenic, and current ACMG/AMP practice does not use database assertions alone to apply PP5; PP5 was therefore not assessed.

Benign

BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, so its observed population frequency is 0 and is below the benign stand-alone threshold of 1%; BA1 is not met.

BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, so its observed population frequency is 0 and is below the benign strong threshold of 0.3%; BS1 is not met.

BS2 No evidence was identified showing this variant in healthy adult individuals in a context sufficient to apply BS2, so BS2 was not assessed.

BS3 No well-established functional studies demonstrating no damaging effect for this specific variant were identified, so BS3 was not assessed.

BS4 No non-segregation data were identified for this variant, so BS4 was not assessed.

BP2 No phase information demonstrating this variant in trans with a pathogenic variant for a dominant disorder, or in cis for any disorder, was identified, so BP2 was not assessed.

BP5 No alternate molecular explanation for the phenotype was identified in the available evidence, so BP5 was not assessed.

BP6 Although ClinVar includes Likely benign and Benign submissions for this variant, database assertions alone were not used to apply BP6; BP6 was not assessed.

N/A · 9 PVS1 · PS1 · PM3 · PM4 · PM5 · PP2 · BP1 · BP3 · BP4

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Likely benign (2 clinical laboratories) and as Benign (1 clinical laboratory).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB oncogenicity for this specific variant: Unknown Oncogenic Effect (variant has not been individually curated).

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

Hotspots ↗

Literature · how each cited paper was used

1papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.

Customizing local and systemic therapies for women with early breast cancer: the

PMID 34242744 ↗

Found

Structured finding pending for this record — see source link.

Applied to

→BP7 supporting

Sources & reference links

6Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

Cancer hotspots

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