LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-09-09
Case ID: NM_007294.4_c.2501G_A_20260909_142115
Framework: ACMG/AMP 2015 with ENIGMA Table 3 adaptations
Variant classification summary

NM_007294.4:c.2501G>A

BRCA1  · NP_009225.1:p.(Gly834Glu)  · NM_007294.4
GRCh37: chr17:41245047 C>T  ·  GRCh38: chr17:43093030 C>T
Gene: BRCA1 Transcript: NM_007294.4
Final call
Likely Benign
BS1 supporting BP1 strong
All criteria require review: For research and educational purposes only.
Variant details
Gene
BRCA1
Transcript
NM_007294.4
Protein
NP_009225.1:p.(Gly834Glu)
gnomAD AF
6.816083478433292e-06 (v4.1)
ClinVar
Uncertain significance
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
BP1 (Strong): missense p.(Gly834Glu) at residue 834, outside all clinically important BRCA1 domains (RING, coiled-coil, BRCT), with no predicted splice impact (SpliceAI max delta 0.001).
2
BS1 (Supporting): gnomAD v4.1 group-maximum FAF 5.137e-05 falls in the supporting frequency range (>0.00002 to <=0.0001).
3
Likely Benign: one Strong (-4) plus one Supporting (-1) benign criterion totals -5 ENIGMA points, within the -6 to -2 range.
Final determination: Under ENIGMA BRCA1/BRCA2 v1.2 Table 3, one Strong (Benign) criterion plus one Supporting (Benign) criterion yields Likely Benign.
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 Not met: p.(Gly834Glu) is a missense change with no predicted premature termination or nonsense-mediated decay, and SpliceAI max delta is only 0.001.
cspec clinvar spliceai PMID:26306726 PMID:32438681
PS1 Not assessed Not assessed: no pathogenic or likely pathogenic comparator with the same amino-acid change (p.Gly834Glu) was identified.
cspec spliceai
PS2 N/A Not applicable: the ENIGMA BRCA1/2 specification does not use PS2, and no de novo or parental-testing evidence was available.
cspec
PS3 Not assessed Not assessed: no calibrated functional assay result for p.(Gly834Glu) meeting the specification's Table 9 requirement was available.
cspec vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 PMID:26306726 PMID:32438681
PS4 Not assessed Not assessed: the two cohort observations provide no matched case-control comparison meeting the required p<=0.05 and OR>=4.
cspec PMID:26306726 PMID:32438681
PM1 N/A Not applicable: the ENIGMA specification does not apply PM1, and no authoritative domain-table entry applies to this variant.
cspec
PM2 Not met Not met: the variant is present in population databases (2 alleles in gnomAD v2.1, 11 in gnomAD v4.1) rather than absent from controls.
cspec gnomad_v2 gnomad_v4
PM3 Not assessed Not assessed: no Fanconi anemia phenotype or co-occurring pathogenic BRCA1 variant in the same gene was documented.
cspec PMID:26306726 PMID:32438681
PM4 N/A Not applicable: the ENIGMA specification does not use PM4, and this missense change produces no protein-length alteration.
cspec clinvar
PM5 N/A Not applicable: the ENIGMA PM5 rule applies only to protein-termination-codon variants, and p.(Gly834Glu) is a missense change.
cspec pm5_candidates
PM6 N/A Not applicable: the ENIGMA specification does not use PM6, and no unconfirmed de novo evidence was available.
cspec
PP1 Not assessed Not assessed: no affected-relative genotypes or quantitative co-segregation data were available.
cspec
PP2 N/A Not applicable: the ENIGMA BRCA1/2 specification provides its own rule in place of PP2.
cspec
PP3 Not met Not met: residue 834 lies outside the clinically important RING, coiled-coil, and BRCT domains, and SpliceAI max delta 0.001 is below the 0.2 threshold.
cspec spliceai vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
PP4 Not assessed Not assessed: no combined, clinically calibrated multifactorial likelihood ratio for this variant was available.
cspec vcep_pmid_31853058_brca1_clinical_history_lr PMID:26306726 PMID:32438681
PP5 N/A Not applicable: the ENIGMA specification does not use PP5, and ClinVar has no expert-panel submission for this exact variant.
cspec clinvar
BA1 Not met Not met: the maximum group allele frequency of 5.137e-05 (gnomAD v4.1) is far below the required >0.001.
cspec gnomad_v2 gnomad_v4
BS1 Met Met (Supporting): the gnomAD v4.1 group-maximum FAF of 5.137e-05 falls in the supporting range (>0.00002 to <=0.0001).
cspec gnomad_v2 gnomad_v4
BS2 Not assessed Not assessed: no homozygous or compound-heterozygous case observations or Fanconi anemia phenotype data were available.
cspec
BS3 Not assessed Not assessed: no calibrated functional assay demonstrating absence of damaging effect was available for this variant.
cspec vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 PMID:26306726 PMID:32438681
BS4 Not assessed Not assessed: no affected-relative genotypes or quantitative non-segregation data were available.
cspec
BP1 Met Met (Strong): residue 834 lies outside every clinically important BRCA1 domain (RING, coiled-coil, BRCT), with SpliceAI max delta 0.001.
cspec spliceai
BP2 N/A Not applicable: the ENIGMA specification applies BP2 only in the context of BS2.
cspec
BP3 N/A Not applicable: the ENIGMA specification does not use BP3, and this missense change is not an in-frame indel.
cspec clinvar
BP4 Not met Not met: despite SpliceAI max delta 0.001, the BP4 missense pathway requires location within a clinically important domain, and residue 834 is outside them.
cspec spliceai vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
BP5 Not assessed Not assessed: no combined, clinically calibrated multifactorial likelihood ratio against pathogenicity was available.
cspec vcep_pmid_31853058_brca1_clinical_history_lr
BP6 N/A Not applicable: the ENIGMA specification does not use BP6, and ClinVar's benign assertion is a single-submitter record, not an expert-panel one.
cspec clinvar
BP7 Not assessed Not assessed: no variant-specific mRNA assay was available for BP7_Strong (RNA), and the routine BP7 pathway applies only to silent variants.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
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