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BARD1c.1658C>GPathogenic
Print report
Variant interpretation report

BARD1 c.1658C>G, p.(Ser553Ter)

NM_000465.4:c.1658C>G NP_000456.2:p.(Ser553Ter) 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.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.

PM2Moderate
PM2 · moderate

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%).

PP5Supporting
PP5 · supporting

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.

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
0.070 maximum delta

Recorded SpliceAI maximum delta score: 0.070. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded. 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.

27 criteria with recorded statuses: 3 met · 16 not met · 0 not assessed · 8 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

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.

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

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

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

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

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.

Met · 3

PVS1 Very strongNM_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. Details ▾Hide ▴
Evidence considered
  • Nonsense variant p.Ser553Ter in exon 7/11
  • NMD 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
  • PMID:35353237)
  • Transcript NM_000465.4 is MANE select
  • biologically relevant
Sources
pvs1_generic_framework ↗pvs1_gene_contextpvs1_variant_assessmentPMID:25741868 ↗
PM2 ModerateNM_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%). 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 SupportingClinVar 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. Details ▾Hide ▴
Evidence considered
  • ClinVar Variation ID 1777393: Pathogenic/Likely pathogenic
  • 4 submitters: 3 Pathogenic
  • 1 Likely pathogenic
  • Review status: criteria provided
  • multiple submitters
  • no conflicts
  • Submitter SCV003278129 (Labcorp/Invitae) cites PVS1
  • PM2 in evidence signals
Sources
clinvar ↗

Not met · 16 · evaluated, threshold not reached

PS2 No de novo data are available for this variant. PS2 requires confirmed de novo occurrence with both maternity and paternity confirmed. Details ▾Hide ▴
Still missing
  • Parental testing and de novo confirmation absent
PS3 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. Details ▾Hide ▴
Still missing
  • No variant-specific functional assay data available
PS4 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. Details ▾Hide ▴
Still missing
  • No case-control data
  • Literature does not report this variant in affected cohorts
PM1 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. Details ▾Hide ▴
Evidence considered
  • Hotspot analysis: residue not significant
  • exact variant not listed
PM6 No de novo data are available for this variant. PM6 requires a confirmed de novo occurrence without confirmation of paternity and maternity. Details ▾Hide ▴
Still missing
  • No de novo observations
PP1 No segregation data are available for this variant. PP1 requires cosegregation with disease in multiple affected family members. Details ▾Hide ▴
Still missing
  • No segregation analysis data
PP3 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. Details ▾Hide ▴
Evidence considered
  • BayesDel score: 0.279 (intermediate
  • not definitively damaging)
  • SpliceAI max delta: 0.07 (no splice impact predicted)
Still missing
  • REVEL score unavailable
Sources
bayesdelspliceai ↗
PP4 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. Details ▾Hide ▴
Still missing
  • Proband phenotype and family history not available for review
BA1 The variant is absent from gnomAD. BA1 requires allele frequency >1% in any continental population, which is not met. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1
  • Absent from gnomAD v4.1
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 The variant is absent from gnomAD. BS1 requires allele frequency >0.3%, which is not met. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1
  • Absent from gnomAD v4.1
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS2 No observation of this variant in healthy adult individuals is documented. BS2 requires observation in a healthy adult for a fully penetrant disorder. Details ▾Hide ▴
Still missing
  • No observation in healthy adult controls
BS3 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. Details ▾Hide ▴
Still missing
  • No benign functional evidence available
BS4 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. Details ▾Hide ▴
Still missing
  • No segregation data available
BP2 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. Details ▾Hide ▴
Still missing
  • No data on trans configuration with other BARD1 variants
BP4 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. Details ▾Hide ▴
Evidence considered
  • BayesDel 0.279: intermediate
  • not definitively benign
  • SpliceAI max delta 0.07: no splice alteration predicted
Still missing
  • REVEL score unavailable
Sources
bayesdelspliceai ↗
BP6 BP6 requires a reputable source to classify the variant as benign. ClinVar classifies this variant as Pathogenic/Likely pathogenic, not benign. Details ▾Hide ▴
Evidence considered
  • ClinVar: Pathogenic/Likely pathogenic
  • not benign
Sources
clinvar ↗
Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 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. Details ▾Hide ▴

No further detail was recorded.

PM5 N/AThis 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. Details ▾Hide ▴
Sources
pm5_candidates
PP2 N/APP2 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. Details ▾Hide ▴

No further detail was recorded.

BP1 N/ABP1 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. Details ▾Hide ▴

No further detail was recorded.

BP3 N/ASkipped per adjudication directive: variant is a substitution (nonsense), not an in-frame indel. Details ▾Hide ▴

No further detail was recorded.

BP5 N/ABP5 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. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 applies to synonymous (silent) variants with no predicted splice impact. NM_000465.4:c.1658C>G is a nonsense variant, not synonymous. Details ▾Hide ▴

No further detail was recorded.

PS5 N/APS5 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. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
BARD1
Transcript
NM_000465.4
Coding (HGVS c.)
NM_000465.4:c.1658C>G
Protein (HGVS p.)
NP_000456.2:p.(Ser553Ter)
GRCh38
chr2:214752466 G>C
GRCh37
chr2:215617190 G>C
ClinVar
1777393

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 +89 bp
0.030
SpliceAI acceptor gainat +101 bp
0.000
SpliceAI donor lossat -19 bp
0.070
SpliceAI donor gainat -16 bp
0.000
Pangolin splice lossmagnitude shown
-0.090
Pangolin splice gain
0.010

Other predictors

REVEL
Not available
BayesDel
0.279

How the predictions were used

PP3 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. Details ▾Hide ▴
Evidence considered
  • BayesDel score: 0.279 (intermediate
  • not definitively damaging)
  • SpliceAI max delta: 0.07 (no splice impact predicted)
Still missing
  • REVEL score unavailable
Sources
bayesdelspliceai ↗
BP4 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. Details ▾Hide ▴
Evidence considered
  • BayesDel 0.279: intermediate
  • not definitively benign
  • SpliceAI max delta 0.07: no splice alteration predicted
Still missing
  • REVEL score unavailable
Sources
bayesdelspliceai ↗
BP7 N/ABP7 applies to synonymous (silent) variants with no predicted splice impact. NM_000465.4:c.1658C>G is a nonsense variant, not synonymous. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

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

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.
    Review article discussing BRCA1 and its role in genome integrity maintenance. BARD1 is mentioned as a BRCA1-interacting protein. NM_000465.4:c.1658C>G was not identified in this paper.
    Does not name this variant
    PMID 20029420 ↗
  • Identification of a RING protein that can interact in vivo with the BRCA1 gene product.
    Initial identification of BARD1 as a BRCA1-interacting RING domain protein. Full-text extraction was corrupted and unreadable, but this 1996 discovery paper predates clinical variant reporting and does not reference NM_000465.4:c.1658C>G.
    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 16 sequence variants including three suspected pathogenic: c.1690C>T (p.Gln564X), c.1315-2A>G (splice), and c.1977A>G (silent with ESE disruption). NM_000465.4:c.1658C>G (p.Ser553Ter) was not among the variants detected.
    Does not name this variant
    PMID 21344236 ↗
    Quoted passage
    A protein truncating BARD1 nonsense mutation (c.1690C>T, p.Gln564X) was identified in family #1273

    Results, Table 1 (complete variant listing)

  • 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.
    ACMG/AMP standards and guidelines for the interpretation of sequence variants. This is the canonical framework document defining the criteria used in this assessment. NM_000465.4:c.1658C>G is not discussed as an example variant.
    Does not name this variant
    PMID 25741868 ↗
  • American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility.
    American Society of Clinical Oncology · 2003
    ASCO 2003 policy statement on genetic testing for cancer susceptibility. Provides general recommendations on clinical genetic testing. Does not discuss BARD1 or any specific variants.
    Does not name this variant
    PMID 12692171 ↗
  • American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility.
    Robson ME et al. · 2010
    ASCO policy statement update on genetic and genomic testing for cancer susceptibility. Discusses general principles of germline testing, high-penetrance vs intermediate-penetrance mutations, and direct-to-consumer testing. BARD1 and NM_000465.4:c.1658C>G are not mentioned.
    Does not name this variant
    PMID 20065170 ↗
  • Cancer predisposing missense and protein truncating BARD1 mutations in non-BRCA1 or BRCA2 breast cancer families.
    De Brakeleer S et al. · 2010
    Screened 196 high-risk non-BRCA1/2 breast cancer families for BARD1 mutations. Reported missense and protein-truncating BARD1 mutations. Full text was not available for review, but the abstract does not mention NM_000465.4:c.1658C>G or p.Ser553Ter.
    Does not name this variant
    PMID 20077502 ↗
  • BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer.
    Adam MP et al. · 1993
    GeneReviews clinical summary on BRCA1- and BRCA2-associated hereditary breast and ovarian cancer. Covers clinical characteristics, diagnosis, and management of BRCA1/2 syndromes. BARD1 is not a focus of this review and NM_000465.4:c.1658C>G is not discussed.
    Does not name this variant
    PMID 20301425 ↗

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 0.070 Open source ↗
ClinVar Captured ClinVar source record 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 is present in ClinVar (Variation ID: 1777393); submission details unavailable.

In silico

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

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.