No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.BARD1 encodes a protein that partners with BRCA1 to form a complex essential for repairing damaged DNA, particularly double-stranded breaks, and for maintaining genome stability through cell-cycle checkpoints and chromatin regulation. Germline mutations in BARD1 predispose to breast and ovarian cancer, among other cancers, and the gene is generally regarded as a tumor suppressor, although some evidence suggests it can also promote cancer in certain cellular contexts.
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
The applied criteria and their strengths are shown as assessed under the stated framework.
Met (supporting): absent from gnomAD v2.1 and v4.1, satisfying the <=0.0001 PM2 frequency threshold, though this is a synonymous change.
Met at supporting strength: SpliceAI max delta 0.009 is at or below the <=0.1 no-splice-impact BP4 cutoff, counted once and not reused for BP7.
VUS: PM2 (supporting, absent from gnomAD) and BP4 (supporting, SpliceAI 0.009) leave conflicting supporting-level evidence that meets no Pathogenic or Benign combination rule.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1 allele counts were not recorded for this variant.
Absent from gnomAD v2.1.
Not available in gnomAD-Canada v1.0.
Recorded SpliceAI maximum delta score: 0.009. Refer to the recorded PP3/BP4 rationale for interpretation.
1 Likely benign · 1 Benign. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
28 criteria with recorded statuses: 2 met · 9 not met · 9 not assessed · 8 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
The segregation/de novo group contributes no evidence for BARD1 NM_000465.4:c.354T>C. The case is a variant-level classification with no proband, pedigree, parental testing or family genotyping, so PS2, PM6, PP1 and BS4 are all not_assessed rather than met or not met.
No ClinGen CSPEC or gene-specific BARD1 specification exists (cspec URL empty); generic ACMG/AMP 2015 criteria were applied.
The phenotype/prevalence group yields no pathogenic-direction evidence for BARD1 c.354T>C (p.Asn118=): PS4 is not met because no affected carrier or case-control enrichment is reported, and PP4 is not met because no proband phenotype exists for this exact variant.
PP5 and BP6 are both not met by their source restriction: ClinVar variation 3260425 has 0 expert-panel submissions, and both of its two entries are single clinical-laboratory classifications (Ambry: Likely benign; Myriad: Benign), so neither the pathogenic nor the benign expert-panel prerequisite is satisfied. The 2-star aggregate benign label must not be used as BP6.
BP5 is not_assessed because no affected case carrying this variant with an alternate molecular cause is documented; the missing element is case-level clinical information.
No BARD1 CSPEC/VCEP specification exists for this case (generic ACMG/AMP mode), so no gene-specific thresholds or modified strengths apply to any criterion in this group.
This group owns the calibrated computational-evidence criteria PP3, BP4 and BP7. All three were scoped against the variant type before any predictor score was read: NM_000465.4:c.354T>C is the synonymous substitution NP_000456.2:p.(Asn118=) in BARD1 exon 3, so PP3/BP4 are evaluated on the SpliceAI splice path only and BP7 is the synonymous-variant criterion; the REVEL missense path and BayesDel are not applicable to this variant.
The group's only positive contribution to classification is BP4 at supporting strength, from the SpliceAI maximum delta score of 0.009 for this variant (at or below the <= 0.1 no-splice-impact cutoff; Jaganathan et al. 2019, Cell, PMID:30661751). PP3 is not met (0.009 is far below the >= 0.2 supporting cutoff).
BP7 is not counted: the single SpliceAI/Pangolin no-impact prediction that would support it is already credited under BP4, and one prediction may not be double-counted across PP3/BP4/BP7; the conservation element of BP7 is also unverified (no phyloP/GERP/PhastCons data in the case).
Net contribution: one benign supporting criterion (BP4, supporting) and no pathogenic-direction computational evidence. No VCEP/CSPEC specification for BARD1 was available, so generic ACMG/AMP 2015 in-silico calibration was applied throughout.
No governing ClinGen CSPEC/VCEP or local BARD1 framework exists for this case (cspec found = false, gene_vcep_dir = null, final_classification_framework = generic_acmg_fallback), so generic ACMG/AMP 2015 population thresholds were applied.
All population-frequency evidence comes from gnomAD: the variant is absent from gnomAD v2.1 (exomes, all-comers), gnomAD v4.1, and the non-cancer subsets GNOMAD_V2_1_NON_CANCER and GNOMAD_V3_1_NON_CANCER; absence was independently confirmed by direct gnomAD API region queries at the GRCh38 and GRCh37 loci.
Because the variant has no observed alleles and no heterozygous or homozygous carriers, the stand-alone and strong benign frequency criteria cannot be satisfied: BA1 (>= 0.05), BS1 (>= 0.01) and BS2 (healthy adult carrier) are all not met.
PM2 is met at supporting strength because the allele frequency is effectively 0, well below the <= 0.0001 supporting threshold; however, the variant is a synonymous p.(Asn118=) change with no predicted splice impact, so PM2 carries minimal interpretive weight and human review is flagged.
gnomAD-Canada v1.0 timed out during retrieval and contributed no data; this is recorded as a gap but cannot plausibly alter any of the four verdicts.
The literature reviewed for this case (PMID:15604628, PMID:31429903) contains no BARD1- or variant-specific population-frequency data and was not used to support any population criterion.
No criteria match.
PM2 is a frequency-only criterion: the variant must be absent from, or extremely rare in, population databases (generic supporting threshold: allele frequency <= 0.0001). The variant is absent from gnomAD v2.1 (exomes, all-comers), gnomAD v4.1, and the non-cancer subsets GNOMAD_V2_1_NON_CANCER and GNOMAD_V3_1_NON_CANCER, and absence was independently confirmed by direct gnomAD API region queries at both the GRCh38 and GRCh37 coordinates. With an observed allele frequency of effectively 0, the PM2 frequency condition is satisfied and the criterion is met at supporting strength (the ClinGen SVI-recommended strength). Two qualifications are recorded and are the reason human review is flagged. First, the variant is a synonymous change, p.(Asn118=), with no predicted splice impact, so it is not a strong candidate for a loss-of-function mechanism; rarity of a synonymous allele carries little weight toward pathogenicity and PM2 here should not be allowed to shift the overall classification. Second, no BARD1-specific PM2 threshold exists (no ClinGen CSPEC/VCEP and no local BARD1 framework), so the generic supporting threshold was applied, and gnomAD-Canada could not be screened because its query timed out; that cohort is far too small to change an allele-frequency determination at the 0.0001 level.
PM2 supporting pathogenic: population allele frequency <= 0.0001 (ClinGen SVI 2020 downgrade of PM2 to Supporting; PMID:25741868)
Scope determined first, identically to PP3: NM_000465.4:c.354T>C is the synonymous substitution NP_000456.2:p.(Asn118=) in BARD1 exon 3, so BP4 is taken from the splice-prediction path (SpliceAI) only. There is no REVEL arm to use - a synonymous change has no amino-acid substitution to score, and REVEL is not found in this case anyway - and BayesDel carries no generic ACMG-strength calibration and no BARD1-specific one. Crucially, this is not a missense variant, so a clean SpliceAI delta could not have licensed BP4 through the protein-impact path in the reverse direction either; only the splice path is in play. SpliceAI Lookup for this exact variant gives a maximum delta score of 0.009 (DS_AG 0.009, DS_AL 0.000, DS_DG 0.001, DS_DL 0.003), with Pangolin splice-gain 0.015 and splice-loss -0.007. That maximum delta is at or below the recommended SpliceAI no-impact cutoff of <= 0.1, the published BP4 (supporting) calibration for splice predictors (Jaganathan et al. 2019, Cell; PMID:30661751). The two directions agree that no splice consequence is created or strengthened: the largest gain component is 0.009 at a site 138 bp away, and the acceptor-loss and donor-loss components are 0.000 and 0.003. The result is internally consistent with the variant's position - c.354 sits 10 nt inside the exon, upstream of the exon 3/intron 3 donor boundary (exon 3 = c.216-364) - and no cryptic splice-site usage is predicted. BP4 is therefore met at supporting strength: multiple in-silico lines of splice evidence indicate no impact on splicing, which for a synonymous change is the relevant gene-product-level claim. This single SpliceAI/Pangolin prediction is credited here only; it is not also counted under BP7 (see BP7), and the requirement that PP3/BP4 evidence come from one path only is respected. No BARD1 VCEP/CSPEC specification was available (cspec found=false; generic_acmg_fallback, framework_complete=false), so the generic published threshold was applied verbatim.
Generic ACMG/AMP in-silico splice path: SpliceAI max delta <= 0.1 -> BP4 (supporting) (Jaganathan et al. 2019, Cell; PMID:30661751). Met: max delta 0.009.
PS4 requires case-control or case-enrichment evidence showing the variant is significantly more common in affected individuals than controls. BARD1 c.354T>C (p.Asn118=) has no case-level data at all: ClinVar (variation ID 3260425) holds exactly two submissions, both single clinical-laboratory classifications (Ambry Genetics: Likely benign; Myriad Genetics: Benign), neither accompanied by a case observation or cohort, and both flagged as having no valid PMIDs and zero usable criterion leads. The two full-text papers routed to this group were read (paper_extracts for PMID:15604628 and PMID:31429903): neither names BARD1 nor this variant, and neither provides any BARD1 case-control, prevalence, or penetrance data - PMID:15604628 is a genetic-counseling practice guideline whose gene tables omit BARD1, and PMID:31429903 is the USPSTF BRCA1/BRCA2 recommendation statement. No other variant-specific report was identified in the case evidence. With zero affected carriers reported for this variant, no case-control enrichment statistic (odds ratio, prevalence ratio) exists to compare against any threshold, and PS4 cannot be met. No BARD1 gene-specific VCEP/CSpec specification exists for this case, so generic ACMG/AMP governs and no gene-specific numeric PS4 threshold applies.
PS4: the prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (Richards et al. 2015, PMID:25741868).
Scope settled first, before any predictor score was read. NM_000465.4:c.354T>C is BARD1 exon 3 chr2:g.215657031A>G (GRCh37) / g.214792307A>G (GRCh38), and Mutalyzer/VariantValidator normalisation resolves it to NP_000456.2:p.(Asn118=) - a synonymous (silent) substitution, not a missense change and not a frameshift, nonsense or other protein-length-changing variant. PP3 for this variant therefore comes from the splice-prediction path (SpliceAI) only. The REVEL missense protein-impact path does not apply: a synonymous change makes no amino-acid-substitution claim to score, and REVEL is in any case recorded as not found for this variant - an absent missense score is not evidence, and it is not a reason to reach for a splice score in reverse. BayesDel is also unusable: no generic ACMG-strength calibration exists for it and no gene-specific specification supplies one for BARD1 (it is likewise not found in this case). No ClinGen CSPEC and no gene-specific VCEP specification exists for BARD1 (cspec found=false; vcep_materials.json contains no summaries, files, domain tables or index guidance; final classification framework source = generic_acmg_fallback, framework_complete=false, precedence_rank 3), so the generic ACMG/AMP 2015 fallback and its published in-silico calibration govern. SpliceAI Lookup for this exact variant reports DS_AG 0.009, DS_AL 0.000, DS_DG 0.001, DS_DL 0.003, giving a maximum delta score of 0.009 (the source's own summary sentence rounds this to 0.01); the nearest predicted acceptor gain is 138 bp away (DP_AG 138) and the largest single component is a donor gain of only 0.009. Pangolin, reported alongside, is concordant (splice-gain 0.015, splice-loss -0.007), and spliceai_available = true. A maximum delta score of 0.009 is far below the recommended SpliceAI supporting cutoff for PP3 (max delta >= 0.2) and below the high-precision moderate cutoff (>= 0.5) (Jaganathan et al. 2019, Cell; PMID:30661751). No in-silico tool predicts a splice-altering effect, and no other computational evidence in this case supports a damaging impact. PP3 is therefore not met. The variant does sit near a splice boundary - exon 3 spans c.216-364, so c.354 is only 10 nt upstream of the exon 3/intron 3 junction - but position alone is not evidence, and the calibrated predictor applied to that position predicts no gain or loss of a splice site at the variant.
Generic ACMG/AMP in-silico splice path: SpliceAI max delta >= 0.2 -> PP3 (supporting); >= 0.5 -> PP3 (moderate) (Jaganathan et al. 2019, Cell; PMID:30661751). Not met: max delta 0.009.
PP4 requires that the patient's phenotype or family history be highly specific for a disease with a single genetic etiology. This case evaluates a synonymous BARD1 c.354T>C (p.Asn118=) variant for which no proband, family, or clinical phenotype is reported anywhere in the case evidence: ClinVar variation 3260425 carries only two laboratory classification submissions with no accompanying patient phenotype, the case manifest contains no index-patient phenotype data, and OncoKB returned a non-variant-specific 'Unknown Oncogenic Effect' entry for the residue rather than any patient-level presentation. The two full-text papers reviewed (PMID:15604628, PMID:31429903) describe hereditary breast/ovarian cancer risk assessment in general and never mention BARD1 or this variant. With no affected individual carrying this variant and no BARD1-specific phenotype documented, there is nothing to score for phenotype specificity, and PP4 is not met. No BARD1 gene-specific VCEP/CSpec exists, so generic ACMG/AMP applies.
PP4: the patient's phenotype or family history is highly specific for a disease with a single genetic etiology (Richards et al. 2015, PMID:25741868).
PP5 is restricted to an exact-variant ClinVar classification from an expert panel (ClinGen/VCEP), which corresponds to a 3-star review status; ordinary laboratory submissions, aggregate ClinVar labels, and non-expert assertions must never trigger it. For BARD1 c.354T>C (p.Asn118=), ClinVar variation 3260425 has exactly two submissions, both from single clinical laboratories - Ambry Genetics (Likely benign, SCV005098889, review status 'criteria provided, single submitter') and Myriad Genetics, Inc. (Benign, SCV005404377, review status 'criteria provided, single submitter'). The submission audit records expert_panel_submissions = 0, and the aggregate entry carries only 2 stars ('criteria provided, multiple submitters, no conflicts'). There is no ClinGen/VCEP expert-panel classification of this exact variant, and the governing criteria source for this case is generic ACMG with no BARD1 VCEP specification. The expert-panel prerequisite is therefore absent and PP5 is not met; the fact that the aggregate ClinVar label is benign is irrelevant to PP5.
PP5: reputable source reports the variant as pathogenic, restricted to non-laboratory expert-panel assertions (e.g. ClinGen/VCEP 3-star ClinVar classification) - ordinary laboratory submissions or aggregate ClinVar labels must not trigger it.
BA1 requires a stand-alone benign allele frequency of >= 0.05 in a large population database. This variant (BARD1 NM_000465.4:c.354T>C, GRCh38 chr2:214792307 A>G) has no observed alleles in any queried population dataset: gnomAD v2.1 reports the variant as absent (exomes, all-comers), gnomAD v4.1 reports it as absent, and the non-cancer subsets GNOMAD_V2_1_NON_CANCER and GNOMAD_V3_1_NON_CANCER also report absence. Rarity was independently confirmed by a direct gnomAD API region query spanning chr2:214,792,200-214,792,420 (GRCh38) and chr2:215,656,930-215,657,140 (GRCh37), in which neighbouring positions return variants but the position 214792307/215657031 A>G is not present. The estimated population allele frequency is therefore effectively 0, orders of magnitude below the 0.05 stand-alone threshold, and no heterozygous or homozygous genotypes are recorded. BA1 therefore cannot be applied. No gene-specific BARD1 BA1 threshold exists because no ClinGen CSPEC/VCEP and no local BARD1 framework is available for this gene, so the generic ACMG/AMP 2015 stand-alone frequency threshold governs.
BA1 stand-alone benign: population allele frequency >= 0.05 (ACMG/AMP 2015; PMID:25741868)
BS1 requires an allele frequency greater than that expected for the disorder, using the generic default of >= 0.01 in a population database. The variant is absent from gnomAD v2.1 (exomes, all-comers), gnomAD v4.1, and from the non-cancer subsets GNOMAD_V2_1_NON_CANCER and GNOMAD_V3_1_NON_CANCER, and absence was independently confirmed by direct API region queries around chr2:214792307 (GRCh38) and chr2:215657031 (GRCh37). The observed allele frequency is therefore effectively 0, which is below the 0.01 strong-benign threshold, so this criterion is not satisfied. A gene-specific BARD1 BS1 threshold is not available because no ClinGen CSPEC/VCEP or local BARD1 framework exists for this case, so the generic ACMG/AMP/SVI default was applied rather than a Whiffin-style gene-calibrated prevalence-derived threshold. Because BARD1-associated breast cancer is a moderate-penetrance adult-onset condition, even a small non-zero frequency would not justify BS1 at this level, and here there is no frequency at all.
BS1 strong benign: population allele frequency >= 0.01 (generic SVI default; per-gene derivation preferred, Whiffin et al. 2017; PMID:28518168)
BS2 requires the variant to be observed in a healthy adult individual, with full penetrance expected at an early age for the relevant inheritance model, or in the homozygous state for a recessive disorder. BARD1-associated breast cancer predisposition is a dominant, adult-onset, moderate-penetrance condition, so BS2 would need at least one heterozygous carrier among the adult population controls. The variant is absent from gnomAD v2.1 (exomes, all-comers), gnomAD v4.1, and the non-cancer subsets GNOMAD_V2_1_NON_CANCER and GNOMAD_V3_1_NON_CANCER, with absence independently confirmed by direct gnomAD API region queries. There are consequently zero heterozygous adult carriers and zero homozygotes recorded, so the observation BS2 requires simply does not exist in the available population data. BS2 is therefore not met. It is also not applicable in the sense of a recessive mechanism, since no evidence supports a recessive BARD1 disorder for this variant.
BS2 strong benign: observed in a healthy adult individual with full penetrance expected at an early age (ACMG/AMP 2015; PMID:25741868)
BP6 is restricted to an exact-variant ClinVar classification from an expert panel (ClinGen/VCEP), i.e. a 3-star Benign/Likely benign assertion; ordinary laboratory submissions, aggregate ClinVar labels, and non-expert assertions must never trigger it. ClinVar variation 3260425 for BARD1 c.354T>C (p.Asn118=) reports an aggregate Benign/Likely benign label at only 2 stars ('criteria provided, multiple submitters, no conflicts'), derived from exactly two single-submitter clinical-laboratory classifications - Ambry Genetics, Likely benign (SCV005098889) and Myriad Genetics, Inc., Benign (SCV005404377) - both with review status 'criteria provided, single submitter'. The submission audit records expert_panel_submissions = 0. No expert panel has classified this exact variant, so the benign aggregate label does not satisfy BP6's source requirement and BP6 is not met. Note this is a defect in the source type, not in the evidence direction: the underlying benign signal is captured by the population/frequency criteria (e.g. rare-variant and synonymous-variant arguments), never by BP6 from laboratory submissions.
BP6: reputable source reports the variant as benign, restricted to non-laboratory expert-panel assertions (e.g. ClinGen/VCEP 3-star ClinVar benign classification) - ordinary laboratory submissions or aggregate ClinVar labels must not trigger it.
Scope: BP7 applies only to a synonymous variant, and NM_000465.4:c.354T>C is synonymous (NP_000456.2:p.(Asn118=), Asn118 AAT>AAC), so BP7 is in scope and was evaluated rather than dismissed. BP7 as defined in the ACMG/AMP 2015 framework (Richards et al., PMID:25741868) requires a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site, and for which the nucleotide is not highly conserved. The case contains exactly one item of in-silico evidence speaking to the first requirement: the SpliceAI result for this variant (maximum delta score 0.009, with Pangolin splice-gain 0.015 and splice-loss -0.007), which does predict no splice impact. That same single prediction, however, is the evidence already credited to BP4 at supporting strength for this variant (SpliceAI max delta <= 0.1). The ACMG/AMP framework states that predictions from different in-silico tools are treated as a single piece of evidence rather than independent pieces, and this framework additionally forbids double-counting one prediction across PP3/BP4/BP7; crediting the identical SpliceAI/Pangolin result under both BP4 and BP7 would count one prediction twice and inflate the benign evidence for this variant. The second BP7 element cannot be established either: no nucleotide-conservation metric for c.354 (phyloP, GERP, PhastCons or equivalent) is present anywhere in the case evidence - gnomAD returns the variant as absent from v2.1, v4.1 and gnomAD-Canada and carries no conservation annotation - so the 'not highly conserved' clause of BP7 is unverified. BP7 is therefore not counted as an independent benign criterion for this variant; the prediction that would support it has already been applied once, under BP4.
BP7 (Richards et al. 2015, PMID:25741868): synonymous variant with no predicted impact on the splice consensus sequence or creation of a new splice site, and the nucleotide not highly conserved. Not credited: the only supporting prediction (SpliceAI max delta 0.009) is already counted under BP4, and the conservation element is unverified.
PS2 (de novo, confirmed) requires a proband carrying NM_000465.4:c.354T>C in whom both parents have been tested and shown not to carry the variant, with a phenotype consistent with the gene-disease association. The case evidence contains no proband, no pedigree, no parental genotypes and no meioses for this variant; the input is a standalone variant-level classification (BARD1, synonymous p.Asn118=). Lacking any trios or parent-child testing, confirmed de novo status can be neither established nor excluded. PS2 is therefore not assessable.
PS3 requires well-established functional studies demonstrating a damaging effect on gene or protein function (Richards et al. 2015, PMID:25741868). NM_000465.4:c.354T>C in BARD1 is a synonymous substitution, NP_000456.2:p.(Asn118=), located in exon 3 (NG_012047.3:g.22405T>C). No functional assay data of any kind were identified for this exact variant: no RNA/splicing assay (RT-PCR or minigene), no BARD1 protein-abundance or stability assay, and no homology-directed repair (HDR) or BARD1/BRCA1 complementation assay. The two full-text publications retrievable for this case (PMID:15604628, NSGC cancer risk assessment guideline; PMID:31429903, USPSTF BRCA-related cancer recommendation statement) were screened in full and are clinical practice/recommendation documents containing no BARD1 mention and no experimental data. The ClinVar record (VCV003260425) carries two single-submitter classifications (Ambry: Likely benign; Myriad: Benign) with no criterion-level evidence and zero PMIDs usable for criterion leads, so it supplies no PS3 evidence. The SpliceAI max delta score of 0.009 is an in-silico prediction, not a functional assay, and therefore cannot be counted as PS3 evidence; it is adjudicated under the in-silico criteria instead. No CSPEC/VCEP specification exists for BARD1 (gene_vcep_dir null; cspec found=false), so the generic ACMG/AMP 2015 definition of PS3 governs. Because the criterion specifically requires experimental functional evidence and none exists in this case, PS3 cannot be assessed.
ACMG/AMP 2015 PS3: well-established functional studies show a damaging effect (Richards et al. 2015, PMID:25741868)
PM3 (Richards et al. 2015, PMID:25741868) is defined for recessive disorders as a variant detected in trans with a pathogenic variant; for a dominant disorder it has no defined trans-observation context. NM_000465.4:c.354T>C is a synonymous substitution (NP_000456.2:p.(Asn118=)) in BARD1, a gene whose associated phenotype (hereditary breast and ovarian cancer susceptibility) is inherited in an autosomal dominant, reduced-penetrance manner, so a trans configuration with a second pathogenic BARD1 allele is not the expected disease mechanism. More decisively, no individual-level allelic evidence exists anywhere in this case: there is no affected-proband genotype, no second pathogenic or likely pathogenic BARD1 variant, no family or segregation data, and no phase determination. The two ClinVar submissions for variation 3260425 (Ambry Genetics, Likely benign; Myriad Genetics, Benign) are both single-submitter, neither is expert-panel reviewed, neither supplies a validated PMID, and neither contributes a co-occurrence or phase observation. The variant is absent from gnomAD v2.1 and v4.1, so no homozygous genotype is reported, and neither reviewed full-text paper names BARD1 or this variant. No BARD1 CSPEC/VCEP specification could be retrieved (framework_complete = false), so the generic ACMG/AMP 2015 fallback governs. Because the required allelic observation was never collected rather than searched for and found absent, PM3 is recorded as not assessed, with the missing data identified as gaps.
ACMG/AMP 2015 PM3 (PMID:25741868): for recessive disorders, detected in trans with a pathogenic variant.
PM6 (assumed de novo, without confirmation of parentage) requires at least a proband whose parents are unavailable for testing but whose de novo occurrence is reasonably assumed from the pedigree. No proband, pedigree or parental-genotype information exists for NM_000465.4:c.354T>C in this case, so neither a confirmed nor an assumed de novo occurrence can be evaluated. PM6 is not assessable.
PP1 (co-segregation with disease in multiple affected family members) requires a pedigree with genotyped affected relatives and tracked meioses showing the variant co-segregating with disease. No pedigree, family genotyping or segregation data exist for NM_000465.4:c.354T>C in this case. Without any family structure or informative meioses, co-segregation cannot be counted. PP1 is not assessable.
BS3 requires well-established functional studies demonstrating no damaging effect on gene or protein function (Richards et al. 2015, PMID:25741868). NM_000465.4:c.354T>C is a synonymous substitution (NP_000456.2:p.(Asn118=)) in BARD1 exon 3. No functional assay data were identified for this exact variant in any source assembled for this case: no RNA/splicing assay, no BARD1 protein stability assay, and no HDR or complementation assay. The two retrievable full-text publications (PMID:15604628, NSGC guideline; PMID:31429903, USPSTF recommendation statement) were screened in full, do not mention BARD1 or this variant, and contain no experimental data. The ClinVar record (VCV003260425) provides two single-submitter classifications (Benign and Likely benign) but no criterion-level evidence and no functional study citations. An absent or uninformative functional result is not the same as a functional study showing no damaging effect; the absence of a SpliceAI-predicted splice impact (max delta 0.009) is an in-silico prediction, not functional evidence, and is adjudicated under the in-silico criteria. Because BS3 specifically requires experimental functional evidence of no damaging effect and none exists, BS3 cannot be assessed. No CSPEC/VCEP specification for BARD1 is available, so the generic ACMG/AMP 2015 definition governs.
ACMG/AMP 2015 BS3: well-established functional studies show no damaging effect (Richards et al. 2015, PMID:25741868)
BS4 (lack of segregation with disease) requires a family in which the variant is demonstrated not to segregate with the phenotype among affected relatives. No pedigree or family genotype data exist for NM_000465.4:c.354T>C in this case, so non-segregation cannot be demonstrated. BS4 is not assessable; its absence does not by itself argue for pathogenicity.
BP2 (Richards et al. 2015, PMID:25741868) is met when a variant is observed in trans with a pathogenic variant for a fully penetrant dominant disorder, observed in cis with a pathogenic variant in any inheritance pattern, or observed in trans with a pathogenic variant for a recessive disorder. Every arm of BP2 requires a phase-resolved, individual-level genotype in which this allele is placed with or opposite a known pathogenic allele, and none is available. The case contains no proband genotype, no family or segregation data, and no cis/trans phase result, and no source reports a pathogenic BARD1 allele co-occurring with NM_000465.4:c.354T>C. ClinVar holds only two single-submitter entries for variation 3260425 with no criteria, PMIDs, or allelic observations; the variant is absent from gnomAD v2.1 and v4.1; OncoKB lists no variant-specific oncogenicity (Unknown Oncogenic Effect) and provides no allelic information; and the two reviewed full-text papers (PMID:15604628, PMID:31429903) do not mention BARD1 or this variant, so neither can establish cis/trans configuration. Additionally, BARD1-related disease is a reduced-penetrance dominant condition, so the fully penetrant dominant arm of BP2 would not apply even if trans were demonstrated. Because no phase or co-occurrence evidence was collected at all, BP2 is recorded as not assessed rather than refuted; no BARD1 CSPEC/VCEP specification exists, so the generic ACMG/AMP 2015 definition governs.
ACMG/AMP 2015 BP2 (PMID:25741868): observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder, or in cis with a pathogenic variant in any inheritance pattern, or in trans with a pathogenic variant for a recessive disorder.
BP5 applies when a variant is found in a case with an alternate molecular basis for the disease (a different pathogenic variant, or a non-genetic explanation, established for the affected individual). This requires case-level information: an affected proband carrying the variant plus documented evidence of the competing cause. No such case exists in the evidence for BARD1 c.354T>C (p.Asn118=): ClinVar variation 3260425 contains only two laboratory classification submissions with no patient, family, or co-occurring-variant information; the case manifest reports no index-patient clinical data; and the two full-text papers reviewed (PMID:15604628, PMID:31429903) are cancer-risk-assessment guidelines that never mention BARD1 or this variant and report no BARD1 case. Because the prerequisite - an affected carrier with an established alternate cause - is absent from the record rather than evaluated and refuted, BP5 is not_assessed rather than not_met.
BP5: variant found in a case with an alternate molecular basis for disease (Richards et al. 2015, PMID:25741868).
deterministic_prefilter: requires_null_variant_class
deterministic_prefilter: requires_missense
deterministic_prefilter: requires_missense
deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel
deterministic_prefilter: requires_missense
deterministic_prefilter: requires_missense
deterministic_prefilter: requires_missense
deterministic_prefilter: requires_repeat_region_indel
Every interpreted variant in BARD1, mapped onto the exon structure of NM_000465.4. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
Absent from gnomAD v4.1.
Absent from gnomAD v2.1.
Not available in gnomAD-Canada v1.0.
Scope determined first, identically to PP3: NM_000465.4:c.354T>C is the synonymous substitution NP_000456.2:p.(Asn118=) in BARD1 exon 3, so BP4 is taken from the splice-prediction path (SpliceAI) only. There is no REVEL arm to use - a synonymous change has no amino-acid substitution to score, and REVEL is not found in this case anyway - and BayesDel carries no generic ACMG-strength calibration and no BARD1-specific one. Crucially, this is not a missense variant, so a clean SpliceAI delta could not have licensed BP4 through the protein-impact path in the reverse direction either; only the splice path is in play. SpliceAI Lookup for this exact variant gives a maximum delta score of 0.009 (DS_AG 0.009, DS_AL 0.000, DS_DG 0.001, DS_DL 0.003), with Pangolin splice-gain 0.015 and splice-loss -0.007. That maximum delta is at or below the recommended SpliceAI no-impact cutoff of <= 0.1, the published BP4 (supporting) calibration for splice predictors (Jaganathan et al. 2019, Cell; PMID:30661751). The two directions agree that no splice consequence is created or strengthened: the largest gain component is 0.009 at a site 138 bp away, and the acceptor-loss and donor-loss components are 0.000 and 0.003. The result is internally consistent with the variant's position - c.354 sits 10 nt inside the exon, upstream of the exon 3/intron 3 donor boundary (exon 3 = c.216-364) - and no cryptic splice-site usage is predicted. BP4 is therefore met at supporting strength: multiple in-silico lines of splice evidence indicate no impact on splicing, which for a synonymous change is the relevant gene-product-level claim. This single SpliceAI/Pangolin prediction is credited here only; it is not also counted under BP7 (see BP7), and the requirement that PP3/BP4 evidence come from one path only is respected. No BARD1 VCEP/CSPEC specification was available (cspec found=false; generic_acmg_fallback, framework_complete=false), so the generic published threshold was applied verbatim.
Generic ACMG/AMP in-silico splice path: SpliceAI max delta <= 0.1 -> BP4 (supporting) (Jaganathan et al. 2019, Cell; PMID:30661751). Met: max delta 0.009.
Scope settled first, before any predictor score was read. NM_000465.4:c.354T>C is BARD1 exon 3 chr2:g.215657031A>G (GRCh37) / g.214792307A>G (GRCh38), and Mutalyzer/VariantValidator normalisation resolves it to NP_000456.2:p.(Asn118=) - a synonymous (silent) substitution, not a missense change and not a frameshift, nonsense or other protein-length-changing variant. PP3 for this variant therefore comes from the splice-prediction path (SpliceAI) only. The REVEL missense protein-impact path does not apply: a synonymous change makes no amino-acid-substitution claim to score, and REVEL is in any case recorded as not found for this variant - an absent missense score is not evidence, and it is not a reason to reach for a splice score in reverse. BayesDel is also unusable: no generic ACMG-strength calibration exists for it and no gene-specific specification supplies one for BARD1 (it is likewise not found in this case). No ClinGen CSPEC and no gene-specific VCEP specification exists for BARD1 (cspec found=false; vcep_materials.json contains no summaries, files, domain tables or index guidance; final classification framework source = generic_acmg_fallback, framework_complete=false, precedence_rank 3), so the generic ACMG/AMP 2015 fallback and its published in-silico calibration govern. SpliceAI Lookup for this exact variant reports DS_AG 0.009, DS_AL 0.000, DS_DG 0.001, DS_DL 0.003, giving a maximum delta score of 0.009 (the source's own summary sentence rounds this to 0.01); the nearest predicted acceptor gain is 138 bp away (DP_AG 138) and the largest single component is a donor gain of only 0.009. Pangolin, reported alongside, is concordant (splice-gain 0.015, splice-loss -0.007), and spliceai_available = true. A maximum delta score of 0.009 is far below the recommended SpliceAI supporting cutoff for PP3 (max delta >= 0.2) and below the high-precision moderate cutoff (>= 0.5) (Jaganathan et al. 2019, Cell; PMID:30661751). No in-silico tool predicts a splice-altering effect, and no other computational evidence in this case supports a damaging impact. PP3 is therefore not met. The variant does sit near a splice boundary - exon 3 spans c.216-364, so c.354 is only 10 nt upstream of the exon 3/intron 3 junction - but position alone is not evidence, and the calibrated predictor applied to that position predicts no gain or loss of a splice site at the variant.
Generic ACMG/AMP in-silico splice path: SpliceAI max delta >= 0.2 -> PP3 (supporting); >= 0.5 -> PP3 (moderate) (Jaganathan et al. 2019, Cell; PMID:30661751). Not met: max delta 0.009.
Scope: BP7 applies only to a synonymous variant, and NM_000465.4:c.354T>C is synonymous (NP_000456.2:p.(Asn118=), Asn118 AAT>AAC), so BP7 is in scope and was evaluated rather than dismissed. BP7 as defined in the ACMG/AMP 2015 framework (Richards et al., PMID:25741868) requires a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site, and for which the nucleotide is not highly conserved. The case contains exactly one item of in-silico evidence speaking to the first requirement: the SpliceAI result for this variant (maximum delta score 0.009, with Pangolin splice-gain 0.015 and splice-loss -0.007), which does predict no splice impact. That same single prediction, however, is the evidence already credited to BP4 at supporting strength for this variant (SpliceAI max delta <= 0.1). The ACMG/AMP framework states that predictions from different in-silico tools are treated as a single piece of evidence rather than independent pieces, and this framework additionally forbids double-counting one prediction across PP3/BP4/BP7; crediting the identical SpliceAI/Pangolin result under both BP4 and BP7 would count one prediction twice and inflate the benign evidence for this variant. The second BP7 element cannot be established either: no nucleotide-conservation metric for c.354 (phyloP, GERP, PhastCons or equivalent) is present anywhere in the case evidence - gnomAD returns the variant as absent from v2.1, v4.1 and gnomAD-Canada and carries no conservation annotation - so the 'not highly conserved' clause of BP7 is unverified. BP7 is therefore not counted as an independent benign criterion for this variant; the prediction that would support it has already been applied once, under BP4.
BP7 (Richards et al. 2015, PMID:25741868): synonymous variant with no predicted impact on the splice consensus sequence or creation of a new splice site, and the nucleotide not highly conserved. Not credited: the only supporting prediction (SpliceAI max delta 0.009) is already counted under BP4, and the conservation element is unverified.
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
5 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.
Hereditary breast cancer; hereditary breast/ovarian cancer; OMIM numbers: 113705, 600185, 114480 — Breast cancer in females and males, ovarian and prostate cancers and other cancers, depending on the gene in question — BRCA1, BRCA2, probably other gene(s)
Table I (Selected Hereditary Syndromes Associated With an Increased Risk of Common Cancers)
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
Absent from gnomAD v4.1.
Absent from gnomAD v2.1.
Not available in gnomAD-Canada v1.0.
This variant has been reported in ClinVar as Likely benign (1 clinical laboratory) and as Benign (1 clinical laboratory). (ClinVarID = 3260425)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.