About BRCA1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRCA1 c.302-10_302-5delinsATTTTA, p.?
Classification
Uncertain significance
Variant description:
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.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
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 ClinGen BRCA1 VCEP v1.2. 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: 0
Benign evidence criteria: 1
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Intronic variant at positions c.302-10 to c.302-5, outside the canonical donor/acceptor splice sites (±1,2). SpliceAI predicts no significant splice impact (max delta score 0.01, ≤0.1 threshold). Satisfies ENIGMA BP4_Supporting rule for intronic variants outside native splice sites with no predicted splicing impact.
Recorded classification: Uncertain significance
ENIGMA BRCA1/2 VCEP v1.2 Table 3 rules applied. Only one criterion is met: BP4 at supporting strength. A single supporting benign criterion does not satisfy any ENIGMA Table 3 Likely Benign combination rule (which requires at minimum 2 Supporting benign, or 1 Strong benign + 1 Supporting benign, or 1 Strong benign alone with multiple evidence types). No pathogenic criteria are met. The variant therefore defaults to Variant of Uncertain Significance (VUS).
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
No listed criterion applied
SpliceAI score
0.010 maximum delta
Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
No screenshot for this evidence
Functional evidence
Not recorded
No standalone functional evidence summary is recorded in evidence_summary.functional.
No listed criterion applied
OncoKB ↗
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Context only
COSMIC ↗
For specialists
Technical detail
ACMG/AMP criteria under ClinGen BRCA1 VCEP v1.2, with the data and sources behind each one.
28 criteria with recorded statuses: 1 met · 17 not met · 0 not assessed · 10 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_007294.4:c.302-10_302-5delinsATTTTA is an intronic indel in BRCA1 intron 5 (legacy intron 6), spanning positions -10 to -5 relative to exon 6. SpliceAI predicts no significant splice impact (max delta score 0.01).
This variant is absent from gnomAD v2.1 and v4.1 population databases, though intronic coverage in exome data cannot be reliably confirmed (ac=null, an=null).
The variant has not been reported in ClinVar (0 submissions) and has not been identified in COSMIC somatic cancer databases.
Under ENIGMA BRCA1/2 VCEP v1.2, BP4_Supporting is met: the variant is intronic, outside canonical donor/acceptor splice sites (±1,2), and SpliceAI predicts no splicing impact (max delta 0.01 ≤ 0.1).
PVS1 is not met: the variant is an intronic indel outside the canonical splice consensus (±1,2) and does not qualify as a null variant under ENIGMA criteria. No functional or mRNA splicing data are available for PVS1_RNA.
PM2 is not met: intronic positions lack reliable coverage depth confirmation in gnomAD exome data. PS3/BS3 are not met: no functional assay data exist for this variant in ENIGMA Table 9 or Supplementary Table 4. PP4/BP5 are not met: the variant is not listed in the Li et al. 2020 (PMID:31853058) clinical-history LR table.
With only BP4_Supporting met, this variant is classified as a Variant of Uncertain Significance (VUS) under ENIGMA BRCA1/2 VCEP v1.2 criteria.
No criteria match.
Met · 1
BP4 SupportingIntronic variant at positions c.302-10 to c.302-5, outside the canonical donor/acceptor splice sites (±1,2). SpliceAI predicts no significant splice impact (max delta score 0.01, ≤0.1 threshold). Satisfies ENIGMA BP4_Supporting rule for intronic variants outside native splice sites with no predicted splicing impact. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.01 (≤0.1)
- Intronic positions -10 to -5
- outside canonical ±1
- 2 splice consensus
Sources
Not met · 17 · evaluated, threshold not reached
PVS1 Intronic indel at positions c.302-10 to c.302-5, outside the canonical splice acceptor consensus (±1,2). Does not meet ENIGMA VCEP v1.2 PVS1 criteria for null variants (nonsense, frameshift, canonical ±1,2 splice site, initiation codon, or exon deletion). SpliceAI predicts no significant splice impact (max delta score 0.01). Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.01
- ENIGMA Table 4: canonical splice sites at c.302-2 and c.302-1 only
- positions -10 to -5 not covered by PVS1 splice rules
Sources
spliceai ↗vcep_specifications_table4_v1_2_2024_11_18
PS1 No previously classified pathogenic variant with the same predicted splicing impact identified at this intronic location. ENIGMA PS1 requires a comparator pathogenic/likely pathogenic variant with the same predicted effect on splicing. Details ▾Hide ▴
PS3 No functional assay data available for this intronic indel. Not present in ENIGMA Table 9 curated functional assay results. No variant-specific or systematic-range functional studies identified in the literature. ENIGMA ST3 splicing references catalogue nearby variants (c.302-2del, c.302-3C>G) but not c.302-10_302-5delinsATTTTA. Details ▾Hide ▴
Evidence considered
- ENIGMA Table 9: variant not listed
- ST4 functional assay: no data for this variant or nearby c.302- intronic positions
- ST3 splicing refs: c.302-2del and c.302-3C>G characterized but not c.302-10_302-5delinsATTTTA
Still missing
- No functional or splicing assay data for this specific intronic indel
Sources
vcep_specifications_table9_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18
PS4 No case-control data available. Variant absent from ClinVar with zero submissions. No disease-association reports identified. No case-control odds ratio or prevalence data sufficient for ENIGMA PS4 (p≤0.05 and OR≥4). Details ▾Hide ▴
Evidence considered
- ClinVar: 0 submissions
- absent from database
Still missing
- No case-control studies identified for this variant
Sources
PM2 Variant positions (c.302-10 to c.302-5) lie within intron 5. gnomAD v2.1 and v4.1 report null allele counts (ac=null, an=null), indicating insufficient exome capture coverage for reliable intronic frequency assessment. ENIGMA PM2_Supporting requires adequate read depth (≥25) across the variant region; intronic coverage in exome data cannot be confirmed. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: ac=null
- an=null
- gnomAD v4.1: ac=null
- Intronic position with uncertain exome coverage
Still missing
- Intronic coverage depth not available in gnomAD exome data
Sources
PM5 ENIGMA VCEP v1.2 repurposes PM5 for protein termination codon (PTC) variants only (PM5_PTC), applicable when an exon harbors a previously proven pathogenic PTC. This intronic indel at positions -10 to -5 does not create a PTC and is not eligible for PM5_PTC assessment. ENIGMA ST1 assigns PM5_Strong(PTC) to exon 6(7) but only for PTC-generating variants. Details ▾Hide ▴
Evidence considered
- ST1 PM5_PTC: exon 6(7) assigned PM5_Strong for PTC variants
- Variant is intronic and does not create a protein termination codon
Sources
vcep_specifications_table4_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18
PP1 No co-segregation data available. No family studies or quantitative co-segregation analysis (Bayes score) identified for this variant. Details ▾Hide ▴
Evidence considered
- No co-segregation data identified in any source
Still missing
- No family segregation studies available
PP3 SpliceAI max delta score 0.01, well below the ENIGMA threshold of ≥0.2 for predicted splicing impact (PP3). BayesDel not applicable for indels. ENIGMA PP3 for predicted splicing impact is not met. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.01 (threshold ≥0.2 not met)
- BayesDel not available for indel variants
Sources
PP4 Variant not present in the Li et al. 2020 (PMID:31853058) BRCA1 clinical-history likelihood ratio table. No clinical-history LR data available. ENIGMA PP4 requires LR≥2.08 (supporting) from multifactorial likelihood clinical data. Details ▾Hide ▴
Evidence considered
- Li et al. 2020 clinical-history LR table: variant c.302-10_302-5delinsATTTTA not listed
- Nearby variants: c.302-2delA LR=2.60
- c.302-3C>G LR=0.51
- c.302-5T>C LR=0.41
Still missing
- No clinical-history LR computed for this specific intronic indel
Sources
vcep_pmid_31853058_brca1_clinical_history_lrPMID:31853058 ↗
BA1 Variant absent from gnomAD v2.1 and v4.1. ENIGMA BA1 requires filter allele frequency (FAF) > 0.1% in a non-founder population. Allele frequency does not meet this threshold. Details ▾Hide ▴
BS1 Variant absent from gnomAD. ENIGMA BS1_Strong requires FAF > 0.01% and BS1_Supporting requires FAF > 0.002%. Neither threshold is met. Details ▾Hide ▴
BS2 No proband observations available to assess BS2. ENIGMA BS2 requires observation of the variant in trans with a pathogenic variant, in absence of Fanconi Anemia phenotype, with point-based scoring per proband. No such observations documented. Details ▾Hide ▴
Evidence considered
- No proband data available for BS2 assessment
Still missing
- No homozygous or compound heterozygous observations reported
BS3 No well-established functional studies demonstrating no damaging effect for this intronic indel. Not present in ENIGMA Table 9 curated benign functional assay results. No mRNA splicing studies showing normal transcript profile. Details ▾Hide ▴
Evidence considered
- ENIGMA Table 9: variant not listed for BS3
- ST3 splicing refs: no data for c.302-10_302-5delinsATTTTA
Still missing
- No benign functional or splicing assay data for this specific intronic indel
Sources
vcep_specifications_table9_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18
BS4 No segregation data available. ENIGMA BS4 requires lack of segregation in affected family members as measured by quantitative co-segregation analysis (Bayes score). No family studies identified for this variant. Details ▾Hide ▴
Evidence considered
- No segregation data identified
Still missing
- No family segregation studies available
BP1 ENIGMA BP1 applies to coding variants (silent substitution, missense, or in-frame insertion/deletion/delins) outside clinically important functional domains with no predicted splicing impact. This variant is a purely intronic indel at positions -10 to -5 and does not fall within the BP1 rule scope. Details ▾Hide ▴
BP5 Variant not present in the Li et al. 2020 (PMID:31853058) BRCA1 clinical-history likelihood ratio table. ENIGMA BP5 requires LR≤0.48 (supporting) from multifactorial likelihood clinical data. No clinical-history LR data available. Details ▾Hide ▴
Evidence considered
- Li et al. 2020 clinical-history LR table: variant not listed
Still missing
- No clinical-history LR computed for this specific intronic indel
Sources
vcep_pmid_31853058_brca1_clinical_history_lrPMID:31853058 ↗
BP7 ENIGMA BP7_Supporting applies to intronic variants outside conserved acceptor motif positions (≤-21) when BP4 is met. This variant at positions -10 to -5 lies within the conserved acceptor region (-21 to -1) and does not qualify for BP7_Supporting. BP7_Strong requires mRNA assay data showing no damaging effect on transcript profile; no such data available. Details ▾Hide ▴
Evidence considered
- Variant at positions -10 to -5
- within conserved acceptor motif (-21 to -1)
- No mRNA splicing assay data available for BP7_Strong
Still missing
- No mRNA splicing assay data to assess transcript-level impact
Sources
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PS2 VCEPENIGMA VCEP v1.2: de novo criterion not applicable for BRCA1/2. BRCA1/2-related cancers occur relatively commonly; no calibration data exist for de novo occurrences. Details ▾Hide ▴
PM1 VCEPENIGMA VCEP v1.2: PM1 not applicable for BRCA1/2. Hotspot/domain analysis is captured by bioinformatic code application (PP3/BP4). Details ▾Hide ▴
PM4 VCEPENIGMA VCEP v1.2: PM4 not applicable for BRCA1/2. Protein length changes due to in-frame deletions/insertions are assessed via the bioinformatic code framework (PP3/BP4). Details ▾Hide ▴
PM6 VCEPENIGMA VCEP v1.2: de novo criterion not applicable for BRCA1/2 (same rationale as PS2). BRCA1/2-related cancers are common; no calibration data for de novo predictive capacity. Details ▾Hide ▴
PP2 VCEPENIGMA VCEP v1.2: PP2 not applicable for BRCA1/2. Missense constraint (Z-score) is captured within the bioinformatic code framework. Details ▾Hide ▴
PP5 VCEPENIGMA VCEP v1.2: PP5 not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
BP2 VCEPENIGMA VCEP v1.2: BP2 not applicable for BRCA1/2. Details ▾Hide ▴
BP3 VCEPENIGMA VCEP v1.2: BP3 not applicable for BRCA1/2. In-frame deletions/insertions in repetitive regions are captured by bioinformatic tool prediction and domain analysis. Details ▾Hide ▴
BP6 VCEPENIGMA VCEP v1.2: BP6 not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
PS5 N/APS5 (novel missense at same codon as established pathogenic missense) does not apply to intronic indel variants. Not defined as a separate criterion in the ENIGMA BRCA1/2 VCEP v1.2 specification. Details ▾Hide ▴
Evidence considered
- Intronic indel
- PS5 applies only to coding missense variants at the same residue
Sources
Identifiers
- Gene
- BRCA1
- Transcript
- NM_007294.4
- Coding (HGVS c.)
- NM_007294.4:c.302-10_302-5delinsATTTTA
- Protein (HGVS p.)
- NP_009225.1:p.?
- GRCh38
- chr17:43104266 AAAATA>TAAAAT
- GRCh37
- chr17:41256283 AAAATA>TAAAAT
Gene diagram
Every interpreted variant in BRCA1, mapped onto the exon structure of NM_007294.4. Select a row to find it on the plot.
BRCA1NM_007294.4
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in BRCA1
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
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
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP4 SupportingIntronic variant at positions c.302-10 to c.302-5, outside the canonical donor/acceptor splice sites (±1,2). SpliceAI predicts no significant splice impact (max delta score 0.01, ≤0.1 threshold). Satisfies ENIGMA BP4_Supporting rule for intronic variants outside native splice sites with no predicted splicing impact. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.01 (≤0.1)
- Intronic positions -10 to -5
- outside canonical ±1
- 2 splice consensus
Sources
PP3 SpliceAI max delta score 0.01, well below the ENIGMA threshold of ≥0.2 for predicted splicing impact (PP3). BayesDel not applicable for indels. ENIGMA PP3 for predicted splicing impact is not met. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.01 (threshold ≥0.2 not met)
- BayesDel not available for indel variants
Sources
BP7 ENIGMA BP7_Supporting applies to intronic variants outside conserved acceptor motif positions (≤-21) when BP4 is met. This variant at positions -10 to -5 lies within the conserved acceptor region (-21 to -1) and does not qualify for BP7_Supporting. BP7_Strong requires mRNA assay data showing no damaging effect on transcript profile; no such data available. Details ▾Hide ▴
Evidence considered
- Variant at positions -10 to -5
- within conserved acceptor motif (-21 to -1)
- No mRNA splicing assay data available for BP7_Strong
Still missing
- No mRNA splicing assay data to assess transcript-level impact
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
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 0.010
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
ClinGen CSpec
Captured ClinGen CSpec source record
Open source ↗
All source links
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/1530970787
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_007294.4%3Ac.302-10_302-5…
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-41256283-AAAATA-TAAAAT?dat…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-43104266-AAAATA-TAAAAT?…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/17-43104266-AAAATA-TAAAAT
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_007294.4%3Ac.302-…
- OncoKB ↗www.oncokb.org/gene/BRCA1/?
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=BRCA1+c.302-10_302-5delinsATTTTA
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 absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
Somatic
This variant has not previously been reported in somatic cancers (COSMIC).