LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-07-31
Case ID: NM_007294.4_c.302-10_302-5delinsATTTTA_20260731_213454
Framework: ACMG/AMP 2015 with ENIGMA Table 3 adaptations
Variant classification summary

NM_007294.4:c.302-10_302-5delinsATTTTA

BRCA1  · NP_009225.1:p.?  · NM_007294.4
GRCh37: chr17:41256283 AAAATA>TAAAAT  ·  GRCh38: chr17:43104266 AAAATA>TAAAAT
Gene: BRCA1 Transcript: NM_007294.4
Final call
VUS
BP4 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
BRCA1
Transcript
NM_007294.4
Protein
NP_009225.1:p.?
gnomAD AF
ClinVar
OncoKB
Classification rationale
Interpretation summary
Generated evidence synthesis
1
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).
2
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).
3
The variant has not been reported in ClinVar (0 submissions) and has not been identified in COSMIC somatic cancer databases.
4
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).
5
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.
6
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.
7
With only BP4_Supporting met, this variant is classified as a Variant of Uncertain Significance (VUS) under ENIGMA BRCA1/2 VCEP v1.2 criteria.
Final determination: ENIGMA BRCA1/2 VCEP v1.2 Table 3: a single Supporting (Benign) criterion (BP4) does not meet any Likely Benign combination. No pathogenic criteria are met. Result: VUS.
Criteria assessment
ACMG/AMP criteria review
Criteria shown when status is available
All criteria require review: For research and educational purposes only.
Criterion Status Rationale Evidence used
PVS1 Not met 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).
spliceai vcep_specifications_table4_v1_2_2024_11_18
PS1 Not met 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.
clinvar cspec
PS2 N/A ENIGMA 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.
cspec
PS3 Not met 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.
vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18
PS4 Not met 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).
clinvar
PS5 N/A PS5 (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.
cspec
PM1 N/A ENIGMA VCEP v1.2: PM1 not applicable for BRCA1/2. Hotspot/domain analysis is captured by bioinformatic code application (PP3/BP4).
cspec
PM2 Not met 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.
gnomad_v2 gnomad_v4
PM4 N/A ENIGMA 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).
cspec
PM5 Not met 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.
vcep_specifications_table4_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18
PM6 N/A ENIGMA 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.
cspec
PP1 Not met No co-segregation data available. No family studies or quantitative co-segregation analysis (Bayes score) identified for this variant.
PP2 N/A ENIGMA VCEP v1.2: PP2 not applicable for BRCA1/2. Missense constraint (Z-score) is captured within the bioinformatic code framework.
cspec
PP3 Not met 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.
spliceai cspec
PP4 Not met 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.
vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058
PP5 N/A ENIGMA VCEP v1.2: PP5 not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
cspec
BA1 Not met 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.
gnomad_v2 gnomad_v4
BS1 Not met Variant absent from gnomAD. ENIGMA BS1_Strong requires FAF > 0.01% and BS1_Supporting requires FAF > 0.002%. Neither threshold is met.
gnomad_v2 gnomad_v4
BS2 Not met 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.
BS3 Not met 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.
vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18
BS4 Not met 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.
BP1 Not met 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.
cspec
BP2 N/A ENIGMA VCEP v1.2: BP2 not applicable for BRCA1/2.
cspec
BP3 N/A ENIGMA 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.
cspec
BP4 Met 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.
spliceai cspec
BP5 Not met 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.
vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058
BP6 N/A ENIGMA VCEP v1.2: BP6 not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
cspec
BP7 Not met 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.
cspec spliceai
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