Variant classification summary

NM_000465.4:c.-4G>A

BARD1 · NP_000456.2:p.? · NM_000465.4

GRCh37: chr2:215674297 C>T · GRCh38: chr2:214809573 C>T

Gene: BARD1 Transcript: NM_000465.4

Final call

VUS

PM2 supporting

Variant details

Gene

BARD1

Transcript

NM_000465.4

Protein

NP_000456.2:p.?

gnomAD AF

5.116109787830394e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

VUS: PM2 supporting was assigned because the variant is rare in the default gnomAD datasets.

2

VUS: PM2 supporting alone does not meet a generic ACMG/AMP combination threshold for another classification.

3

VUS: no other criterion was met or applied at a classification-changing strength.

Final determination: Under the generic ACMG/AMP 2015 fallback, one supporting criterion alone does not meet any benign, likely benign, likely pathogenic, or pathogenic combination threshold, resulting in 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: NM_000465.4:c.-4G>A is a 5′-UTR SNV with protein consequence p.? rather than a nonsense, frameshift, or canonical splice-site loss-of-function variant.	pvs1_variant_assessment pvs1_generic_framework
PS1	N/A	Not applicable: c.-4G>A is a 5' UTR variant with protein consequence p.?, so no amino-acid change exists for PS1 comparison.	clinvar
PS2	Not assessed	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	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	Not assessed: no case-control enrichment, odds ratio, or variant-specific affected-case series is available for NM_000465.4:c.-4G>A.
PM1	N/A	Not applicable: the 5' UTR substitution has protein consequence p.?, so no missense residue can be evaluated against a critical domain.
PM2	Met	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 gnomad_v4 gnomad_canada generic_acmg_combination_rules PMID:25741868
PM3	Not assessed	Not assessed: no affected-proband biallelic observation or phase-confirmed pathogenic variant in trans is documented for BARD1 c.-4G>A.
PM4	N/A	Not applicable: the 5′-UTR SNV has protein consequence p.? and produces no documented in-frame insertion, deletion, or protein-length change.	pvs1_variant_assessment
PM5	N/A	Not applicable: protein consequence p.? provides no codon or residue for comparison with pathogenic alternate substitutions.
PM6	Not assessed	Not assessed: no apparently de novo BARD1 c.-4G>A occurrence without confirmed parental testing is documented.
PP1	Not assessed	Not assessed: no informative affected-relative genotypes or meioses are documented to demonstrate segregation of BARD1 c.-4G>A.
PP2	N/A	Not applicable: c.-4G>A is a 5' UTR substitution, not a missense change, so gene-level missense mechanism does not apply.
PP3	N/A	Not applicable: the 5-prime UTR variant has predicted protein consequence p.(=), outside PP3's missense or splice-region/intronic scope.
PP4	Not assessed	Not assessed: no patient phenotype, family history, or variant-specific phenotype correlation is documented for PP4.
PP5	Not met	Not met: ClinVar variation 184470 has zero expert-panel submissions and no expert-panel Pathogenic or Likely pathogenic classification.	clinvar
BA1	Not met	Not met: gnomAD v4.1 total allele frequency is 5.11611e-05, far below the BA1 threshold of >=0.05.	gnomad_v2 gnomad_v4 generic_acmg_combination_rules
BS1	Not met	Not met: the highest reported frequency is 0.0002716505 in gnomAD-Canada, below the generic BS1 threshold of >=0.01.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	Not met: all available population datasets report zero homozygotes, with no qualifying healthy-adult genotype observation.	gnomad_v2 gnomad_v4 gnomad_canada
BS3	Not assessed	Not assessed: no validated benign functional assay was identified, while the SpliceAI maximum delta of 0.002 is not experimental evidence.
BS4	Not assessed	Not assessed: no informative unaffected-relative testing or age- and phenotype-qualified non-segregation data are documented.
BP1	N/A	Not applicable: the variant is a 5' UTR substitution rather than a missense variant required for BP1 assessment.
BP2	Not assessed	Not assessed: no documented co-occurrence of BARD1 c.-4G>A with another pathogenic variant and no phase information is available.
BP3	N/A	Not applicable: this 5′-UTR SNV is not an in-frame insertion or deletion in a repetitive protein-coding region.	pvs1_variant_assessment
BP4	N/A	Not applicable: the 5-prime UTR variant has predicted protein consequence p.(=), outside BP4's missense or splice-region/intronic scope.
BP5	Not assessed	Not assessed: no affected case with this exact variant and a confirmed alternate molecular basis for disease is documented.
BP6	Not met	Not met: ClinVar variation 184470 has zero expert-panel submissions; its Benign and Likely benign labels are ordinary laboratory assertions.	clinvar
BP7	N/A	Not applicable: this is a 5-prime UTR variant, not a synonymous coding variant eligible for BP7.

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.