LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-04-26
Case ID: NM_007294.4_c.442-22_442-13del_20260426_040326
Framework: ACMG/AMP 2015 with ENIGMA Table 3 adaptations
Variant classification summary

NM_007294.4:c.442-22_442-13del

BRCA1  · NP_009225.1:p.?  · NM_007294.4
GRCh37: chr17:41251909 GGTAAAGAACA>G  ·  GRCh38: chr17:43099892 GGTAAAGAACA>G
Gene: BRCA1 Transcript: NM_007294.4
Final call
Likely Pathogenic
PVS1_Strong PM2_Supporting PP3_Supporting 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.442-22_442-13del (NP_009225.1:p.?) variant has been reported in ClinVar as pathogenic, including an expert-panel pathogenic classification from the ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel.
2
This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population controls.
3
Published RNA studies reported that this intronic deletion inserts 59 nucleotides from intron 7 and causes a frameshift with premature termination, and later functional work showed an impaired DNA-damage response associated with the variant.
4
SpliceAI predicts splice disruption with a maximum delta score of 0.66, which is above the ENIGMA PP3 threshold of 0.2 for non-canonical intronic variants.
Final determination: Likely Pathogenic based on one strong pathogenic criterion and at least two supporting pathogenic criteria under the ENIGMA BRCA1/2 Table 3 combination rules.
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 deletion has published RNA evidence showing insertion of 59 nucleotides from intron 7, producing a frameshift and premature termination of BRCA1. Because loss of function is an established disease mechanism for BRCA1, this supports PVS1 at RNA-based strong weight for a non-canonical splice variant, although the proportion of functional transcript retained was not quantitatively reported.
cspec PMID:10323242
PS1 Not assessed Available evidence does not establish that this variant has the same predicted splicing consequence as a different previously classified pathogenic or likely pathogenic variant under the ENIGMA PS1 framework.
cspec
PS2 N/A This criterion is not used in the ENIGMA BRCA1 specification.
cspec
PS3 Not assessed Available functional evidence for this variant is primarily splicing and transcript-based, which is captured under the ENIGMA RNA framework rather than applying PS3 directly from the available materials.
cspec PMID:32745242
PS4 Not assessed This variant has been reported in affected families, but the available evidence does not provide the case-control statistics or ENIGMA-calibrated proband-counting data required to apply PS4.
cspec PMID:32745242
PM1 N/A This criterion is not used in the ENIGMA BRCA1 specification.
cspec
PM2 Met This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, supporting rarity in population controls consistent with PM2_Supporting under the BRCA1 ENIGMA framework.
cspec gnomad_v2 gnomad_v4
PM3 Not assessed No evidence was identified showing this variant in trans with another BRCA1 variant in an individual with BRCA1-related Fanconi anemia features, so PM3 cannot be assessed from the available data.
cspec
PM4 N/A This criterion is not used in the ENIGMA BRCA1 specification.
cspec
PM5 N/A ENIGMA PM5 in BRCA1 is used for protein termination codon variants by exon-based weighting. This intronic deletion is not directly a protein termination codon variant in the submitted DNA description, so PM5 was not applied from the available evidence.
cspec vcep_specifications_table4_v1_2_2024_11_18
PM6 N/A This criterion is not used in the ENIGMA BRCA1 specification.
cspec
PP1 Not assessed Segregation has been mentioned in the literature, but no quantitative segregation likelihood ratio was available from the reviewed materials to support PP1 at any ENIGMA strength.
cspec PMID:32745242
PP2 N/A This criterion is not used in the ENIGMA BRCA1 specification.
cspec
PP3 Met SpliceAI predicts splice disruption for this intronic variant with a maximum delta score of 0.66, which is above the ENIGMA PP3 threshold of 0.2 for non-canonical intronic variants and supports a deleterious splicing effect.
cspec spliceai
PP4 Not assessed Although this variant has been observed in families with hereditary breast and ovarian cancer, no exact variant-level clinical-history likelihood ratio meeting ENIGMA PP4 thresholds was identified in the available structured resources.
cspec vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058
PP5 Met Expert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Pathogenic.
cspec clinvar
BA1 Not met This variant is absent from gnomAD v2.1 and gnomAD v4.1, so it does not meet the ENIGMA BA1 threshold of filter allele frequency greater than 0.1%.
cspec gnomad_v2 gnomad_v4
BS1 Not met This variant is absent from gnomAD v2.1 and gnomAD v4.1, so it does not meet the ENIGMA BS1 thresholds of filter allele frequency above 0.002% or 0.01% in a non-founder population.
cspec gnomad_v2 gnomad_v4
BS2 Not assessed No evidence was identified showing this variant in individuals without features of BRCA1-related Fanconi anemia in the biallelic context required for ENIGMA BS2.
cspec
BS3 Not assessed No well-established functional study showing no damaging effect was identified for this variant, so BS3 is not supported by the available evidence.
cspec
BS4 Not assessed No quantitative evidence showing lack of segregation with disease was identified, so BS4 cannot be applied from the available materials.
cspec
BP1 N/A ENIGMA BP1 is intended for silent, missense, or in-frame variants outside key functional domains without predicted splice impact, and it does not apply to this intronic deletion.
cspec
BP2 N/A This criterion is not used in the ENIGMA BRCA1 specification.
cspec
BP3 N/A This criterion is not used in the ENIGMA BRCA1 specification.
cspec
BP4 Not met SpliceAI predicts splice impact for this intronic variant with a maximum delta score of 0.66, which is above the ENIGMA BP4 threshold of 0.1 for no predicted splice impact, so BP4 is not met.
cspec spliceai
BP5 Not assessed No exact variant-level clinical-history likelihood ratio meeting ENIGMA BP5 benign thresholds was identified in the available structured resources.
cspec vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058
BP6 N/A This criterion is not used in the ENIGMA BRCA1 specification.
cspec
BP7 Not met This intronic deletion does not meet BP7 because benign splicing evidence was not identified and BP4 is not met; SpliceAI predicts splice impact with a maximum delta score of 0.66 rather than the no-impact profile required for BP7 application.
cspec spliceai
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