Classification rationale

PM2 VUS

BARD1 c.-4G>A unknown · exon 1

VUS: PM2 supporting was assigned because the variant is rare in the default gnomAD datasets. VUS: PM2 supporting alone does not meet a generic ACMG/AMP combination threshold for another classification. VUS: no other criterion was met or applied at a classification-changing strength.

PM2 → VUS

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 · 16 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

PM2 supporting review Pathogenic

Met, supporting: gnomAD v4.1 AF 5.11611e-05 is below the PM2 threshold of <=0.0001, although gnomAD-Canada reports 0.0002716505.

gnomAD v2.1 reports AF 3.86024e-05 from 7 of 181336 alleles, with zero homozygotes; the highest reported ancestry AF is 9.19166e-05 in European non-Finnish individuals.gnomAD v4.1 reports AF 5.11611e-05 from 79 of 1544142 alleles, with zero homozygotes; the highest reported ancestry AF is 6.53212e-05 in European non-Finnish individuals.Both default all-comers gnomAD frequencies are below the supplied PM2 supporting threshold of <=0.0001, the ClinGen SVI recommendation supplied for this adjudication (PMID:25741868).

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗PMID:25741868 ↗

Assessed · not applied · 5 not met · 11 not assessed

Pathogenic

PS2 Not assessed: no proband-level de novo observation or confirmed absence of BARD1 c.-4G>A in both biological parents is documented.

PS3 Not assessed: no validated variant-specific functional assay was identified, and the available SpliceAI maximum delta was 0.002 rather than experimental evidence.

PS4 Not assessed: no case-control enrichment, odds ratio, or variant-specific affected-case series is available for NM_000465.4:c.-4G>A.

PM3 Not assessed: no affected-proband biallelic observation or phase-confirmed pathogenic variant in trans is documented for BARD1 c.-4G>A.

PM6 Not assessed: no apparently de novo BARD1 c.-4G>A occurrence without confirmed parental testing is documented.

PP1 Not assessed: no informative affected-relative genotypes or meioses are documented to demonstrate segregation of BARD1 c.-4G>A.

PP4 Not assessed: no patient phenotype, family history, or variant-specific phenotype correlation is documented for PP4.

PP5 Not met: ClinVar variation 184470 has zero expert-panel submissions and no expert-panel Pathogenic or Likely pathogenic classification.

Benign

BA1 Not met: gnomAD v4.1 total allele frequency is 5.11611e-05, far below the BA1 threshold of >=0.05.

BS1 Not met: the highest reported frequency is 0.0002716505 in gnomAD-Canada, below the generic BS1 threshold of >=0.01.

BS2 Not met: all available population datasets report zero homozygotes, with no qualifying healthy-adult genotype observation.

BS3 Not assessed: no validated benign functional assay was identified, while the SpliceAI maximum delta of 0.002 is not experimental evidence.

BS4 Not assessed: no informative unaffected-relative testing or age- and phenotype-qualified non-segregation data are documented.

BP2 Not assessed: no documented co-occurrence of BARD1 c.-4G>A with another pathogenic variant and no phase information is available.

BP5 Not assessed: no affected case with this exact variant and a confirmed alternate molecular basis for disease is documented.

BP6 Not met: ClinVar variation 184470 has zero expert-panel submissions; its Benign and Likely benign labels are ordinary laboratory assertions.

N/A · 11 PVS1 · PS1 · PM1 · PM4 · PM5 · PP2 · PP3 · BP1 · BP3 · BP4 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 5.11611e-05; MAF= 0.00512%, 79/1544142 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 6.53212e-05; MAF= 0.00653%, 75/1148172 alleles, homozygotes = 0); grpmax FAF= 5.336e-05.

v2.1

This variant is present in gnomAD v2.1 (AF= 3.86024e-05; MAF= 0.00386%, 7/181336 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 9.19166e-05; MAF= 0.00919%, 7/76156 alleles, homozygotes = 0); grpmax FAF= 4.241e-05.

🇨🇦 CA

This variant is present in gnomAD-Canada v1.0 (AF= 0.00027165054873410846, 5/18406 alleles, homozygotes = 0).

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0051% · 79 / 1,544,142
0 hom · FAF 0.0053%

European (non-Finnish) 75 / 1,148,172	0.0065%
Remaining individuals 2 / 60,000	0.0033%
Admixed American 1 / 52,478	0.0019%
African/African American 1 / 73,214	0.0014%

+ 6 not observed (European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish)

gnomAD v2.1

0.0039% · 7 / 181,336
0 hom · FAF 0.0042%

European (non-Finnish)

7 / 76,156

0.0092%

+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)

gnomAD Canada 🇨🇦

0.027% · 5 / 18,406
0 hom

Latino/Admixed American 1 / 836	0.12%
European (non-Finnish) 4 / 11,736	0.034%

+ 7 not observed (African/African American, Ashkenazi Jewish, East Asian, European (Finnish), Middle Eastern, Remaining individuals, South Asian)

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (5 clinical laboratories) and as Likely benign (4 clinical laboratories) and as Benign (1 clinical laboratory). (ClinVarID = 184470)

ClinVar ↗

In silico

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

SpliceAI ↗

Functional No data

No calibrated functional assay or RNA evidence was identified for this variant.

OncoKB ↗

COSMIC

Somatic evidence

COSMIC

This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant cancer hotspot.

COSMIC ↗

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. 7 further PMIDs triaged but not cited — see Sources & references.

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

PMID 25741868 ↗ CLINVAR · functional

Found

Both default all-comers gnomAD frequencies are below the supplied PM2 supporting threshold of <=0.0001, the ClinGen SVI recommendation supplied for this adjudication (PMID:25741868).

Applied to

→PM2 supporting

Sources & reference links

7Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Triaged references · 7 PMIDs not cited in assessment

26467025 ↗ A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders. CLINVAR

34242744 ↗ Customizing local and systemic therapies for women with early breast cancer: the St. Gallen International Consensus Guidelines for treatment of early breast cancer 2021. CLINVAR

15604628 ↗ Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors. CLINVAR

20301425 ↗ BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer. CLINVAR

25085752 ↗ Development and validation of a new algorithm for the reclassification of genetic variants identified in the BRCA1 and BRCA2 genes. CLINVAR

26389258 ↗ Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Versi CLINVAR

34012068 ↗ ACMG SF v3.0 list for reporting of secondary findings in clinical exome and genome sequencing: a policy statement of the American College of Medical Genetics and Genomics (ACMG). CLINVAR

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