Variant classification summary

NM_000465.4:c.1658C>G

BARD1 · NP_000456.2:p.(Ser553Ter) · NM_000465.4

GRCh37: chr2:215617190 G>C · GRCh38: chr2:214752466 G>C

Gene: BARD1 Transcript: NM_000465.4

Final call

Pathogenic

PVS1 very strong PM2 moderate PP5 supporting

Variant details

Gene

BARD1

Transcript

NM_000465.4

Protein

NP_000456.2:p.(Ser553Ter)

gnomAD AF

ClinVar

Pathogenic/Likely pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000465.4:c.1658C>G (p.Ser553Ter) is a nonsense variant in BARD1 exon 7 of 11, predicted to undergo nonsense-mediated decay and result in loss of function.

2

Loss-of-function variants in BARD1 are an established mechanism for hereditary breast and ovarian cancer susceptibility, supported by germline disease-focused publications.

3

Under ClinGen SVI PVS1 decision tree (PMC6185798), this nonsense variant meets PVS1 at very strong strength.

4

This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting PM2 at moderate strength.

5

ClinVar (Variation ID 1777393) classifies this variant as Pathogenic/Likely pathogenic with four clinical laboratory submissions and no conflicts, meeting PP5 at supporting strength.

6

No published literature was identified that specifically mentions NM_000465.4:c.1658C>G. The papers cited by ClinVar submitters (PMID:20077502, PMID:21344236) describe BARD1 mutation screening in breast cancer cohorts but do not report this variant.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Pathogenic classification based on the observed combination of very strong, strong, moderate, and supporting pathogenic criteria.

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	Met	NM_000465.4:c.1658C>G is a nonsense variant predicted to cause premature termination at codon 553 (NP_000456.2:p.(Ser553Ter)) in exon 7 of 11. The stop codon occurs 344 nucleotides upstream of the final exon-exon junction, predicting nonsense-mediated decay. BARD1 loss of function is an established mechanism for hereditary breast and ovarian cancer susceptibility. Under ClinGen SVI PVS1 recommendations (PMC6185798), this nonsense variant meets PVS1 at very strong strength.	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment PMID:25741868
PS1	N/A	PS1 applies only when a different nucleotide change at the same codon produces the same amino acid change. This is a nonsense variant producing a stop codon; no same-amino-acid change via a different nucleotide substitution is possible.
PS2	Not met	No de novo data are available for this variant. PS2 requires confirmed de novo occurrence with both maternity and paternity confirmed.
PS3	Not met	No well-established in vitro or in vivo functional studies demonstrating a deleterious effect of this specific variant are available. OncoKB annotation of 'Likely Loss-of-function' is a variant-type-based prediction, not experimental functional evidence. The variant is a nonsense change predicted to undergo NMD; functional studies are not required to establish pathogenicity when PVS1 is met.
PS4	Not met	No case-control or cohort data demonstrating statistically significant enrichment of this variant in affected individuals versus controls are available. The ClinVar-submitter-cited papers (PMID:20077502, PMID:21344236) do not mention NM_000465.4:c.1658C>G in their abstracts or full text.
PS5	N/A	PS5 is reserved for situations where a variant in a well-established disease gene establishes a novel disease mechanism. BARD1 is already an established breast/ovarian cancer susceptibility gene; this variant does not define a new disease mechanism.
PM1	Not met	This variant does not lie in a statistically significant mutational hotspot. The residue is not located in a known critical functional domain identified as a hotspot in Cancer Hotspots database.
PM2	Met	NM_000465.4:c.1658C>G is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes/genomes), and gnomAD-Canada v1.0. Under generic ACMG/AMP rules, absence from large population databases meets PM2 at moderate strength (allele frequency <0.1%).	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	This variant is a nonsense change (p.Ser553Ter). PM5 applies to novel missense variants occurring at the same codon as a known pathogenic missense variant. No same-residue missense comparator is applicable for a nonsense variant. The pm5_candidates analysis confirmed no eligible comparators exist.	pm5_candidates
PM6	Not met	No de novo data are available for this variant. PM6 requires a confirmed de novo occurrence without confirmation of paternity and maternity.
PP1	Not met	No segregation data are available for this variant. PP1 requires cosegregation with disease in multiple affected family members.
PP2	N/A	PP2 is specifically defined for missense variants in genes with a low rate of benign missense variation. This variant is a nonsense (stop-gain) change, not a missense variant.
PP3	Not met	Multiple in silico predictors do not support a deleterious effect. REVEL score is unavailable for this variant. BayesDel score is 0.279 (intermediate, not in clearly damaging range). SpliceAI predicts no splice impact (max delta 0.07). The variant is a nonsense change whose pathogenicity is better assessed through PVS1 than through in silico predictors.	bayesdel spliceai
PP4	Not met	No proband phenotype information is available. PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology.
PP5	Met	ClinVar lists this variant (Variation ID: 1777393) as Pathogenic/Likely pathogenic with four clinical testing submissions and no conflicts (3 Pathogenic, 1 Likely pathogenic; review status: criteria provided, multiple submitters, no conflicts). Although no expert panel has reviewed this variant, the multi-submitter consensus from clinical laboratories supports PP5 at supporting strength.	clinvar
BA1	Not met	The variant is absent from gnomAD. BA1 requires allele frequency >1% in any continental population, which is not met.	gnomad_v2 gnomad_v4
BS1	Not met	The variant is absent from gnomAD. BS1 requires allele frequency >0.3%, which is not met.	gnomad_v2 gnomad_v4
BS2	Not met	No observation of this variant in healthy adult individuals is documented. BS2 requires observation in a healthy adult for a fully penetrant disorder.
BS3	Not met	No well-established functional studies demonstrate no deleterious effect for this specific variant. BS3 requires experimental evidence showing the variant does not alter protein function or splicing.
BS4	Not met	No segregation data are available to evaluate non-segregation with disease. BS4 requires that the variant does not segregate with disease in multiple affected family members.
BP1	N/A	BP1 applies specifically to missense variants in genes where primarily truncating variants are known to cause disease. This variant is itself a truncating (nonsense) variant and does not fall under BP1 scope.
BP2	Not met	No observation of this variant in trans with a known pathogenic variant in BARD1 is available. BP2 requires observation in trans with a pathogenic variant for a fully penetrant dominant disorder.
BP3	N/A	Skipped per adjudication directive: variant is a substitution (nonsense), not an in-frame indel.
BP4	Not met	In silico predictors do not provide consistent evidence supporting a benign effect. BayesDel score is 0.279 (intermediate, not in benign range). SpliceAI shows no splice impact (max delta 0.07), but this does not independently support benign effect for a nonsense variant. REVEL is unavailable.	bayesdel spliceai
BP5	N/A	BP5 requires a variant found in a case with an alternate molecular basis for disease. No alternate molecular basis has been identified, and this criterion is only applicable when another pathogenic variant explains the phenotype.
BP6	Not met	BP6 requires a reputable source to classify the variant as benign. ClinVar classifies this variant as Pathogenic/Likely pathogenic, not benign.	clinvar
BP7	N/A	BP7 applies to synonymous (silent) variants with no predicted splice impact. NM_000465.4:c.1658C>G is a nonsense variant, not synonymous.

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