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BARD1c.1788delPathogenic
Print report
Variant interpretation report

BARD1 c.1788del, p.(Lys596AsnfsTer9)

NM_000465.4:c.1788del NP_000456.2:p.(Lys596AsnfsTer9) View identifiers
Classification
Pathogenic

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.

Pathogenic.A pathogenic classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About BARD1

No gene-level summary was recorded for this case.

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.
01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 3 Benign evidence criteria: 0
Pathogenic criteria applied · 3
PVS1Very strong
PVS1 · very strong

NM_000465.4:c.1788del is a frameshift deletion in exon 8 of 11, predicted to cause a premature termination codon (p.Lys596AsnfsTer9) at codon 604, well upstream of the last exon-exon junction, and is expected to trigger nonsense-mediated decay. BARD1 loss of function is an established mechanism for hereditary breast and ovarian cancer susceptibility. The transcript NM_000465.4 is the MANE Select transcript and is biologically relevant. Under the ClinGen SVI PVS1 decision framework (PMC6185798), this null variant in a gene where LOF is a known disease mechanism qualifies for PVS1 at very strong strength.

PM2Moderate
PM2 · moderate

NM_000465.4:c.1788del is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes/genomes), and gnomAD-Canada v1.0. This satisfies the PM2 threshold for a rare variant absent from large population databases (allele frequency <0.1% under generic ACMG).

PP5Supporting
PP5 · supporting

NM_000465.4:c.1788del is classified as Pathogenic by two clinical laboratories and Likely pathogenic by one clinical laboratory in ClinVar (ClinVarID: 801882). While the review status is 'criteria provided, single submitter' (1-star, not expert panel), the concordant classification from three independent clinical testing laboratories provides supporting evidence for pathogenicity. The evidence used by these laboratories is partially verifiable (PM2 — absence from population databases).

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: 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.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

SpliceAI score
0.030 maximum delta

Recorded SpliceAI maximum delta score: 0.030. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
ClinVar submissions
3 reported laboratory submissions

2 Pathogenic · 1 Likely pathogenic. ClinVar API review status: criteria provided, multiple submitters, no conflicts.

Applied · PP5 → ClinVar ↗
Functional evidence
Statement recorded

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

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported

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

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

29 criteria with recorded statuses: 3 met · 16 not met · 0 not assessed · 10 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_000465.4:c.1788del (p.Lys596AsnfsTer9) is a frameshift deletion in exon 8 of the BARD1 gene, predicted to trigger nonsense-mediated decay and remove the C-terminal BRCT domains essential for homology-directed DNA repair and tumor suppression.

BARD1 loss of function is an established mechanism for hereditary breast and ovarian cancer susceptibility, supported by multiple publications identifying deleterious truncating germline BARD1 mutations in affected families.

The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases, indicating it is extremely rare in the general population.

Three independent clinical laboratories in ClinVar classify this variant as Pathogenic or Likely pathogenic (ClinVar Variation ID: 801882), providing additional supporting evidence.

Applying generic ACMG/AMP 2015 classification rules: PVS1 (very strong) + PM2 (moderate) + PP5 (supporting) meets the pathogenic threshold of 1 Very Strong + 1 Moderate + 1 Supporting.

Overall classification: PATHOGENIC.

Met · 3

PVS1 Very strongNM_000465.4:c.1788del is a frameshift deletion in exon 8 of 11, predicted to cause a premature termination codon (p.Lys596AsnfsTer9) at codon 604, well upstream of the last exon-exon junction, and is expected to trigger nonsense-mediated decay. BARD1 loss of function is an established mechanism for hereditary breast and ovarian cancer susceptibility. The transcript NM_000465.4 is the MANE Select transcript and is biologically relevant. Under the ClinGen SVI PVS1 decision framework (PMC6185798), this null variant in a gene where LOF is a known disease mechanism qualifies for PVS1 at very strong strength. Details ▾Hide ▴
Evidence considered
  • Frameshift deletion c.1788del in exon 8/11 produces premature stop at codon 604
  • upstream of NMD boundary
  • BARD1 loss of function is an established germline disease mechanism for hereditary breast/ovarian cancer
  • supported by multiple publications identifying deleterious truncating BARD1 mutations in affected families
  • The BRCT domains (residues 568-777) critical for homology-directed DNA repair and tumor suppression are removed by this truncation
  • NM_000465.4 is the MANE Select transcript
  • biologically relevant
Sources
pvs1_generic_framework ↗pvs1_gene_contextpvs1_variant_assessmentPMID:20077502 ↗PMID:21344236 ↗
PM2 ModerateNM_000465.4:c.1788del is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes/genomes), and gnomAD-Canada v1.0. This satisfies the PM2 threshold for a rare variant absent from large population databases (allele frequency <0.1% under generic ACMG). Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1
  • Absent from gnomAD v4.1
  • Absent from gnomAD-Canada v1.0
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
PP5 SupportingNM_000465.4:c.1788del is classified as Pathogenic by two clinical laboratories and Likely pathogenic by one clinical laboratory in ClinVar (ClinVarID: 801882). While the review status is 'criteria provided, single submitter' (1-star, not expert panel), the concordant classification from three independent clinical testing laboratories provides supporting evidence for pathogenicity. The evidence used by these laboratories is partially verifiable (PM2 — absence from population databases). Details ▾Hide ▴
Evidence considered
  • ClinVar: Pathogenic (Labcorp/Invitae
  • Myriad Genetics)
  • Likely pathogenic (Mendelics)
  • Three independent clinical laboratory submissions with concordant pathogenic/likely pathogenic classification
Still missing
  • No expert panel review
  • ClinVar review status is 1-star
Sources
clinvar ↗

Not met · 16 · evaluated, threshold not reached

PS2 No de novo observation was identified for NM_000465.4:c.1788del in the reviewed literature or ClinVar submissions. Details ▾Hide ▴
Still missing
  • No de novo testing data available for this variant
PS3 No variant-specific functional data was identified for NM_000465.4:c.1788del. The OncoKB annotation of 'Likely Loss-of-function' is a curated inference, not direct experimental functional evidence. No publication was found that directly tested c.1788del or a systematically characterized range encompassing position 596 in a functional assay. Details ▾Hide ▴
Still missing
  • No experimental functional studies for this specific variant
PS4 The variant is reported in ClinVar as Pathogenic/Likely pathogenic by three clinical laboratories, indicating it has been observed in affected individuals. However, no published case-control study or variant-specific case counts are available in the literature. The reviewed publications report different BARD1 variants, not c.1788del. Insufficient case data to meet PS4 threshold. Details ▾Hide ▴
Evidence considered
  • ClinVar: Pathogenic (2 labs)
  • Likely pathogenic (1 lab)
  • but no variant-specific case counts published
Still missing
  • No published case counts or case-control data for this specific variant
Sources
clinvar ↗
PM6 No de novo observation was identified for NM_000465.4:c.1788del in the reviewed literature or ClinVar submissions. Assumed de novo status is not sufficient; a confirmed de novo report is required. Details ▾Hide ▴
Still missing
  • No de novo testing data available
PP1 No cosegregation data was identified for NM_000465.4:c.1788del. The publications reviewed report segregation data for different BARD1 variants (p.Glu652fs in PMID:20077502; p.Gln564X and others in PMID:21344236), not c.1788del. Details ▾Hide ▴
Still missing
  • No family segregation data for this variant
PP3 SpliceAI predicts no significant splice impact (max delta score = 0.03). REVEL and BayesDel scores are unavailable because the variant is not an SNV. No in silico evidence supports a deleterious effect on splicing or protein function beyond the known consequence of the frameshift itself (already captured by PVS1). Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score = 0.03 — no significant splice impact predicted
  • REVEL and BayesDel not applicable (indel
  • not SNV)
Sources
spliceai ↗
PP4 No specific patient phenotype or family history data is available for the individual(s) carrying NM_000465.4:c.1788del. The ClinVar submissions originate from clinical testing laboratories but do not include detailed phenotype descriptions. Details ▾Hide ▴
Still missing
  • No patient phenotype data available
Sources
clinvar ↗
BA1 NM_000465.4:c.1788del is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Does not meet the BA1 threshold of allele frequency >1% in any population. Details ▾Hide ▴
Evidence considered
  • Absent from all gnomAD populations
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 NM_000465.4:c.1788del is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Does not meet the BS1 threshold of allele frequency >0.3% in any population. Details ▾Hide ▴
Evidence considered
  • Absent from all gnomAD populations
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS2 No data on observation of NM_000465.4:c.1788del in healthy adults. The variant is absent from population databases, so healthy adult carrier data is not available. Details ▾Hide ▴
Still missing
  • No healthy adult carrier data
BS3 No functional studies were identified that demonstrate NM_000465.4:c.1788del has no damaging effect on protein function or splicing. The frameshift nature of the variant predicts a severe loss-of-function effect, which is opposite to what BS3 requires. Details ▾Hide ▴
Still missing
  • No functional studies of this variant
BS4 No cosegregation data is available for NM_000465.4:c.1788del. BS4 requires lack of segregation in affected family members, which cannot be assessed without family studies. Details ▾Hide ▴
Still missing
  • No family segregation data
BP2 No data on observation of NM_000465.4:c.1788del in trans with a known pathogenic BARD1 variant. BP2 cannot be assessed without phase information. Details ▾Hide ▴
Still missing
  • No phase data with other BARD1 pathogenic variants
BP4 SpliceAI predicts no significant splice impact (max delta = 0.03), but this is a single computational data point, not 'multiple lines of computational evidence' as required by BP4. Furthermore, the frameshift nature of the variant itself is inherently damaging to the protein, contradicting BP4's requirement for benign computational evidence. REVEL and BayesDel are not applicable to this variant type. Details ▾Hide ▴
Evidence considered
  • SpliceAI shows no splice impact
  • but this alone does not constitute multiple lines of benign computational evidence
Sources
spliceai ↗
BP5 No evidence was identified that NM_000465.4:c.1788del occurs in a case with an alternate molecular basis for disease. The ClinVar submissions report this variant in individuals with hereditary breast/ovarian cancer phenotypes, without indication of an alternative molecular cause. Details ▾Hide ▴
Still missing
  • No alternate molecular diagnosis data
BP6 ClinVar classifies NM_000465.4:c.1788del as Pathogenic/Likely pathogenic, not benign. BP6 requires a reputable source to report the variant as benign. Details ▾Hide ▴
Evidence considered
  • ClinVar classification is Pathogenic
  • opposite to BP6 requirement
Sources
clinvar ↗
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 applies when a different nucleotide change at the same position has been established as pathogenic. This is a frameshift deletion (c.1788del), not an SNV amenable to same-position comparison under PS1 semantics. Details ▾Hide ▴

No further detail was recorded.

PM1 N/AWhile the variant removes the functionally critical BRCT domains (residues 568-777), this domain-level evidence is already fully captured by PVS1 (null variant removing critical functional domains). Applying PM1 would constitute double-counting of the same biological consequence. No independent mutational hotspot evidence exists (cancerhotspots.org negative). Details ▾Hide ▴
Evidence considered
  • The BRCT domains are well-characterized functional domains critical for BARD1 tumor suppression — but this evidence is already captured by PVS1
Sources
PMID:20077502 ↗
PM3 N/ASkipped per directive. Details ▾Hide ▴

No further detail was recorded.

PM4 N/APM4 applies to in-frame deletions/insertions in non-repeat regions or stop-loss variants. c.1788del is a frameshift deletion producing a premature stop codon, which is already addressed by PVS1. Not applicable under PM4 semantics. Details ▾Hide ▴

No further detail was recorded.

PM5 N/APM5 requires a novel missense change at an amino acid residue where a different missense change has been determined to be pathogenic. This is a frameshift deletion (p.Lys596AsnfsTer9), not a missense variant. PM5 is not applicable. The automated pm5_candidates pipeline confirmed this: unable to parse missense residue context. Details ▾Hide ▴
Evidence considered
  • Frameshift variant type does not fit PM5 residue-based semantics
Sources
pm5_candidates
PP2 N/APP2 applies to missense variants in genes with a low rate of benign missense variation where missense variants are a common disease mechanism. This is a frameshift deletion, not a missense variant. Details ▾Hide ▴

No further detail was recorded.

BP1 N/ABP1 applies to missense variants in genes where primarily truncating variants cause disease. This is a truncating (frameshift) variant, not a missense variant. Details ▾Hide ▴

No further detail was recorded.

BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions without known function. This is a frameshift deletion, not an in-frame variant. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 applies to synonymous variants with no predicted splice impact and low nucleotide conservation. This is a frameshift deletion, not a synonymous variant. Details ▾Hide ▴

No further detail was recorded.

PS5 N/APS5 requires a different pathogenic variant at the same codon. This is a frameshift deletion, not an SNV with established same-codon comparators. PM5 is the appropriate criterion for same-residue comparisons, but this variant type does not fit classic PM5 semantics either. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
BARD1
Transcript
NM_000465.4
Coding (HGVS c.)
NM_000465.4:c.1788del
Protein (HGVS p.)
NP_000456.2:p.(Lys596AsnfsTer9)
GRCh38
chr2:214745743 AT>A
GRCh37
chr2:215610467 AT>A
ClinVar
801882

Gene diagram

Every interpreted variant in BARD1, mapped onto the exon structure of NM_000465.4. Select a row to find it on the plot.

BARD1NM_000465.4
Fetching transcript structure from UCSC…
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +68 bp
0.000
SpliceAI acceptor gainat +111 bp
0.000
SpliceAI donor lossat -21 bp
0.030
SpliceAI donor gainat +33 bp
0.020
Pangolin splice lossmagnitude shown
-0.050
Pangolin splice gain
0.010

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 SpliceAI predicts no significant splice impact (max delta score = 0.03). REVEL and BayesDel scores are unavailable because the variant is not an SNV. No in silico evidence supports a deleterious effect on splicing or protein function beyond the known consequence of the frameshift itself (already captured by PVS1). Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score = 0.03 — no significant splice impact predicted
  • REVEL and BayesDel not applicable (indel
  • not SNV)
Sources
spliceai ↗
BP4 SpliceAI predicts no significant splice impact (max delta = 0.03), but this is a single computational data point, not 'multiple lines of computational evidence' as required by BP4. Furthermore, the frameshift nature of the variant itself is inherently damaging to the protein, contradicting BP4's requirement for benign computational evidence. REVEL and BayesDel are not applicable to this variant type. Details ▾Hide ▴
Evidence considered
  • SpliceAI shows no splice impact
  • but this alone does not constitute multiple lines of benign computational evidence
Sources
spliceai ↗
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact and low nucleotide conservation. This is a frameshift deletion, not a synonymous variant. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03).

8 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

  • BRCA1 and its toolbox for the maintenance of genome integrity.
    Comprehensive review of BRCA1 functions in DNA damage response, cell cycle checkpoint control, and genome stability maintenance. Discusses BRCA1-interacting proteins including BARD1 at the gene level. No specific BARD1 variant, including NM_000465.4:c.1788del, was discussed.
    Does not name this variant
    PMID 20029420 ↗
  • Identification of a RING protein that can interact in vivo with the BRCA1 gene product.
    Original identification of BARD1 as a BRCA1-interacting RING domain protein through yeast two-hybrid screening. Describes BARD1 protein structure including the N-terminal RING motif, ankyrin repeats, and C-terminal BRCT domains. No variant-level analysis was performed. NM_000465.4:c.1788del was not mentioned.
    Does not name this variant
    PMID 8944023 ↗
  • Cancer predisposing BARD1 mutations in breast-ovarian cancer families.
    Ratajska M et al. · 2012
    Screened 109 BRCA1/2-negative high-risk breast/ovarian cancer patients from North-Eastern Poland for BARD1 germline mutations. Identified three novel suspected pathogenic variants: a nonsense mutation (c.1690C>T, p.Gln564X), a splice mutation (c.1315-2A>G causing exon 5 skipping), and a silent variant (c.1977A>G) disrupting exonic splicing enhancers and producing an aberrant transcript lacking exons 2–9. NM_000465.4:c.1788del was not identified in this paper.
    Does not name this variant
    PMID 21344236 ↗
    Quoted passage
    Three of the five novel BARD1 variants (c.1315-2A>G, c.1690C>T, c.1977A>G) were found in individual families and interpreted as possibly deleterious based on their character, location within the gene and absence/low frequency amongst controls.

    Results; Table 1 (all variants listed)

  • Cancer predisposing missense and protein truncating BARD1 mutations in non-BRCA1 or BRCA2 breast cancer families.
    De Brakeleer S et al. · 2010
    Reports the first protein-truncating BARD1 germline mutation (p.Glu652fs, a 20-nucleotide duplication in exon 10) in a breast cancer family, along with two candidate missense mutations (p.Ile509Thr, p.Arg658Cys). Demonstrates that truncating BARD1 mutations removing the BRCT domains are associated with hereditary breast cancer and establishes BARD1 LOF as a disease mechanism. NM_000465.4:c.1788del was not identified in this paper.
    Does not name this variant
    PMID 20077502 ↗
    Quoted passage
    Finally, we observed for the first time a protein truncating mutation in BARD1. This frameshift mutation (p.Glu652ValfsX69) originated from a duplication of twenty nucleotides located in exon 10, creating a premature stop codon leading to a hypothetical protein lacking the entire second functional BRCT domain.

    Results: Table 1, Figure 1; Discussion paragraphs 1–3

  • Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women: U.S. Preventive Services Task Force recommendation statement.
    Moyer VA et al. · 2014
    U.S. Preventive Services Task Force recommendation statement on genetic risk assessment and BRCA mutation testing for breast and ovarian cancer susceptibility in asymptomatic women. Addresses BRCA1 and BRCA2 testing guidelines. Does not discuss BARD1 or any specific BARD1 variant including NM_000465.4:c.1788del.
    Does not name this variant
    PMID 24366376 ↗
  • Summaries for patients. Assessing the genetic risk for BRCA-related breast or ovarian cancer in women: recommendations from the U.S. Preventive Services Task Force.
    2014
    Patient summary of the USPSTF recommendation on BRCA-related cancer genetic risk assessment. Summarizes the 2014 USPSTF guidelines for a patient audience. Does not discuss BARD1 or any BARD1 variant including NM_000465.4:c.1788del.
    Does not name this variant
    PMID 24366402 ↗
  • PMID 24432435
    Nelson HD et al. · 2013
    No paper-specific finding is recorded.
    PMID 24432435 ↗
  • Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Versi
    PDQ Cancer Genetics Risk Assessment and Counseling summary covering cancer genetics risk assessment and counseling. General clinical reference document. No full text available for review. Based on the topic and format (PDQ summary), unlikely to discuss specific BARD1 variants including NM_000465.4:c.1788del.
    Does not name this variant
    PMID 26389258 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.030 Open source ↗
ClinVar 2 Pathogenic · 1 Likely pathogenic Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Pathogenic (2 clinical laboratories) and as Likely pathogenic (1 clinical laboratory). (ClinVarID = 801882)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03).

Functional

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

Somatic

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

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.