LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-04-26
Case ID: NM_007294.4_c.5194-12G_A_20260426_031132
Framework: ACMG/AMP 2015 with ENIGMA Table 3 adaptations
Variant classification summary

NM_007294.4:c.5194-12G>A

BRCA1  · NP_009225.1:p.?  · NM_007294.4
GRCh37: chr17:41209164 C>T  ·  GRCh38: chr17:43057147 C>T
Gene: BRCA1 Transcript: NM_007294.4
Final call
Likely Pathogenic
PVS1_Strong PP4_Moderate PP5_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
The BRCA1 c.5194-12G>A (p.?) variant has been reported in ClinVar, where the ClinGen ENIGMA expert panel classified it as pathogenic.
2
This variant is absent from gnomAD v2.1 and is present at very low frequency in gnomAD v4.1 (2/1612068 alleles; AF 1.24064e-06; grpmax FAF 2.8e-07).
3
RNA studies showed retention of 10 nucleotides of intron 19 (r.5193_5194ins5194-10_5194-1), which is consistent with a loss-of-function splice effect and supports PVS1 at Strong strength under the ENIGMA BRCA1/2 RNA framework.
4
SpliceAI predicts a strong splice impact for this variant with a maximum delta score of 0.96.
5
In the ENIGMA BRCA1 clinical-history model, this variant had a likelihood ratio of 12.3447 in 1 proband, which meets PP4 at Moderate strength.
Final determination: PVS1_Strong together with PP4_Moderate meets the ENIGMA Table 3 criteria-combination rule for Likely Pathogenic; PP5_Supporting is additional concordant evidence.
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 Met This intronic variant is outside the canonical +/-1,2 splice site, so default generic PVS1 does not apply. However, BRCA1 loss of function is an established disease mechanism, and RNA studies showed retention of 10 nucleotides of intron 19 (r.5193_5194ins5194-10_5194-1), consistent with a loss-of-function transcript. Under the ENIGMA BRCA1/2 RNA-splicing framework, this supports PVS1 at Strong strength.
cspec pvs1_gene_context pvs1_variant_assessment vcep_appendices_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 PMID:21394826 PMID:21673748
PS1 Not assessed No evidence was identified that this variant is predicted to produce the same protein change or the same splice consequence as a different previously classified pathogenic or likely pathogenic BRCA1 variant under ENIGMA PS1 rules.
cspec vcep_specifications_v1_2_2024_11_18
PS2 N/A This criterion is not applicable in the ENIGMA BRCA1/2 specification.
cspec vcep_specifications_v1_2_2024_11_18
PS3 N/A Available functional evidence is from mRNA splicing studies rather than protein-function assays. Under the ENIGMA BRCA1/2 specification, damaging mRNA-only evidence is applied under PVS1 (RNA) rather than PS3.
cspec vcep_specifications_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 PMID:21394826 PMID:21673748
PS4 Not assessed No case-control study showing a statistically increased prevalence of this variant in affected individuals versus controls was identified.
cspec vcep_specifications_v1_2_2024_11_18
PM1 N/A This criterion is not applicable in the ENIGMA BRCA1/2 specification.
cspec vcep_specifications_v1_2_2024_11_18
PM2 Not met This variant is absent from gnomAD v2.1 and present at very low frequency in gnomAD v4.1 (2/1612068 alleles; AF 1.24064e-06; grpmax FAF 2.8e-07). ENIGMA PM2_Supporting requires absence from the specified population datasets, and this observation does not meet that requirement.
cspec gnomad_v2 gnomad_v4 vcep_specifications_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18
PM3 Not assessed No evidence was identified that this variant was observed in trans with another BRCA1 pathogenic variant in an individual with BRCA1-related Fanconi anemia.
cspec vcep_specifications_v1_2_2024_11_18
PM4 N/A This criterion is not applicable in the ENIGMA BRCA1/2 specification.
cspec vcep_specifications_v1_2_2024_11_18
PM5 N/A This intronic splice-region variant is not a protein-terminating variant eligible for ENIGMA PM5_PTC, and no qualifying missense PM5 scenario was identified.
cspec vcep_specifications_table4_v1_2_2024_11_18 vcep_specifications_v1_2_2024_11_18
PM6 N/A This criterion is not applicable in the ENIGMA BRCA1/2 specification.
cspec vcep_specifications_v1_2_2024_11_18
PP1 Not assessed No quantitative co-segregation data were identified for this variant.
cspec PMID:17924331 vcep_pmid_17924331_easton_2007_ajhg vcep_specifications_v1_2_2024_11_18
PP2 N/A This criterion is not applicable in the ENIGMA BRCA1/2 specification.
cspec vcep_specifications_v1_2_2024_11_18
PP3 N/A SpliceAI predicts a strong splice effect for this variant (max delta score 0.96, above the ENIGMA PP3 threshold of 0.2), but ENIGMA specifies that PP3 should not be applied when PVS1 is met at any strength.
cspec spliceai vcep_appendices_v1_2_2024_11_18 vcep_specifications_v1_2_2024_11_18
PP4 Met Clinical-history likelihood-ratio analysis for BRCA1 reported an LR of 12.3447 in 1 proband for this variant. This value is above the ENIGMA PP4_Moderate threshold of 4.3 and below the PP4_Strong threshold of 18.7, supporting PP4 at Moderate strength.
cspec PMID:31853058 vcep_pmid_31853058_brca1_clinical_history_lr vcep_pmid_31853058_li_2020_geneticsinmedicine
PP5 Met Expert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Pathogenic.
cspec vcep_specifications_v1_2_2024_11_18 clinvar
BA1 Not met The highest observed filter allele frequency is 2.8e-07 in gnomAD v4.1, which is below the ENIGMA BA1 threshold of 0.001.
cspec gnomad_v4 vcep_specifications_v1_2_2024_11_18
BS1 Not met The highest observed filter allele frequency is 2.8e-07 in gnomAD v4.1, which is below the ENIGMA BS1_Supporting threshold of 0.00002 and well below the BS1 threshold of 0.0001.
cspec gnomad_v4 vcep_specifications_v1_2_2024_11_18
BS2 Not assessed No data were identified showing this variant in individuals without features of BRCA1-related Fanconi anemia at the point thresholds required for BS2.
cspec vcep_specifications_v1_2_2024_11_18
BS3 N/A Available functional evidence is from mRNA splicing studies rather than protein-function assays showing no damaging effect. Under the ENIGMA BRCA1/2 specification, benign mRNA-only evidence is applied under BP7 rather than BS3.
cspec vcep_specifications_v1_2_2024_11_18
BS4 Not assessed No quantitative evidence for lack of segregation in affected family members was identified for this variant.
cspec PMID:17924331 vcep_pmid_17924331_easton_2007_ajhg vcep_specifications_v1_2_2024_11_18
BP1 N/A This is an intronic splice-region variant, not a silent, missense, or in-frame protein-coding variant eligible for BP1.
cspec vcep_appendices_v1_2_2024_11_18 vcep_specifications_v1_2_2024_11_18
BP2 N/A This criterion is not applicable in the ENIGMA BRCA1/2 specification.
cspec vcep_specifications_v1_2_2024_11_18
BP3 N/A This criterion is not applicable in the ENIGMA BRCA1/2 specification.
cspec vcep_specifications_v1_2_2024_11_18
BP4 Not met For intronic variants outside the native splice sites, ENIGMA BP4 requires no predicted splice impact with SpliceAI <=0.1. This variant has a SpliceAI maximum delta score of 0.96, which is above that threshold and argues against BP4.
cspec spliceai vcep_specifications_v1_2_2024_11_18
BP5 Not met Clinical-history likelihood-ratio analysis reported an LR of 12.3447 in 1 proband for this variant. This value is above the ENIGMA neutral-zone upper boundary of 2.08 and well above the BP5 threshold of 0.48, so BP5 is not met.
cspec PMID:31853058 vcep_pmid_31853058_brca1_clinical_history_lr vcep_pmid_31853058_li_2020_geneticsinmedicine
BP6 N/A This criterion is not applicable in the ENIGMA BRCA1/2 specification.
cspec vcep_specifications_v1_2_2024_11_18
BP7 Not met ENIGMA BP7 is used for variants with no predicted splice impact or for mRNA studies showing no damaging splice effect. This variant has a SpliceAI maximum delta score of 0.96 and RNA studies showed retention of 10 nucleotides of intron 19, so BP7 is not met.
cspec spliceai vcep_appendices_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 PMID:21394826 PMID:21673748
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