BARD1

Final classification

Pathogenic

BARD1 c.1658C>G · p.Ser553Ter

BARD1

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.

Gene

BARD1

Transcript

NM_000465.4

HGVS · transcript:coding

NM_000465.4:c.1658C>G

Consequence

N/A

GRCh38

chr2:214752466 G>C

GRCh37

chr2:215617190 G>C

Basis gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PVS1 very strong, PM2 moderate, PP5 supporting; combination = 1 very strong + 1 moderate + 1 supporting, which maps to Pathogenic. ▾

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PVS1 very strong, PM2 moderate, PP5 supporting; combination = 1 very strong + 1 moderate + 1 supporting, which maps to Pathogenic.

Classification rationale

PVS1PM2PP5 Pathogenic

BARD1 c.1658C>G

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.¹ Loss-of-function variants in BARD1 are an established mechanism for hereditary breast and ovarian cancer susceptibility, supported by germline disease-focused publications.² Under ClinGen SVI PVS1 decision tree (PMC6185798), this nonsense variant meets PVS1 at very strong strength.³ This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting PM2 at moderate strength.⁴ ClinVar (Variation ID 1777393) classifies this variant as Pathogenic/Likely pathogenic with four clinical laboratory submissions and no conflicts, meeting PP5 at supporting strength.⁵ 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.⁶

PVS1 + PM2 + PP5 → Pathogenic

1 pvs1_variant_assessmentpvs1_gene_context

2 pvs1_gene_context

3 pvs1_generic_framework ↗

4 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

5 clinvar ↗

6 PMID:20077502 ↗PMID:21344236 ↗

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

BARD1 NM_000465.4

Fetching transcript structure from UCSC…

Applied criteria · 3 applied · 16 assessed

Applied · 3

Strength Supporting Moderate Strong Very strong

✓

PVS1 very strong Pathogenic

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.

Nonsense variant p.Ser553Ter in exon 7/11NMD predicted: stop codon >50 nt upstream of last exon-exon junction (344 nt)BARD1 loss of function is established germline disease mechanism per literature review (PMID:28709830

pvs1_generic_framework ↗PMID:25741868 ↗

✓

PM2 moderate Pathogenic

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%).

Absent from gnomAD v2.1Absent from gnomAD v4.1Absent from gnomAD-Canada v1.0

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

✓

PP5 supporting Pathogenic

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 Variation ID 1777393: Pathogenic/Likely pathogenic4 submitters: 3 Pathogenic1 Likely pathogenic

clinvar ↗

Assessed · not applied

Pathogenic

PS2 No de novo data are available for this variant.

PS3 No well-established in vitro or in vivo functional studies demonstrating a deleterious effect of this specific variant are available.

PS4 No case-control or cohort data demonstrating statistically significant enrichment of this variant in affected individuals versus controls are available.

PM1 This variant does not lie in a statistically significant mutational hotspot.

PM6 No de novo data are available for this variant.

PP1 No segregation data are available for this variant.

PP3 Multiple in silico predictors do not support a deleterious effect.

PP4 No proband phenotype information is available.

Benign

BA1 The variant is absent from gnomAD.

BS1 The variant is absent from gnomAD.

BS2 No observation of this variant in healthy adult individuals is documented.

BS3 No well-established functional studies demonstrate no deleterious effect for this specific variant.

BS4 No segregation data are available to evaluate non-segregation with disease.

BP2 No observation of this variant in trans with a known pathogenic variant in BARD1 is available.

BP4 In silico predictors do not provide consistent evidence supporting a benign effect.

BP6 BP6 requires a reputable source to classify the variant as benign.

N/A · 7 PS1 · PM5 · PP2 · BP1 · BP3 · BP5 · BP7

Research & evidence

Population frequency · supports pathogenic

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

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 Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant is present in ClinVar (Variation ID: 1777393); submission details unavailable.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07). BayesDel score = 0.279235.

SpliceAI ↗

Functional Likely Oncogenic

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

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.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 8 PMIDs not cited in assessment

20029420 ↗ BRCA1 and its toolbox for the maintenance of genome integrity. ONCOKB

8944023 ↗ Identification of a RING protein that can interact in vivo with the BRCA1 gene product. ONCOKB

21344236 ↗ Cancer predisposing BARD1 mutations in breast-ovarian cancer families. CLINVAR

25741868 ↗ 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. CLINVAR

12692171 ↗ American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility. CLINVAR

20065170 ↗ American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. CLINVAR

20077502 ↗ Cancer predisposing missense and protein truncating BARD1 mutations in non-BRCA1 or BRCA2 breast cancer families. CLINVAR

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