LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-09-09
Case ID: NM_007294.4_c.2597G_A_v9_20260909
Framework: ACMG/AMP 2015 with ENIGMA Table 3 adaptations
Variant classification summary

NM_007294.4:c.2597G>A

BRCA1  · NP_009225.1:p.(Arg866His)  · NM_007294.4
GRCh37: chr17:41244951 C>T  ·  GRCh38: chr17:43092934 C>T
Gene: BRCA1 Transcript: NM_007294.4
Final call
Benign
BP1 strong BP5 strong BP6 supporting benign
All criteria require review: For research and educational purposes only.
Variant details
Gene
BRCA1
Transcript
NM_007294.4
Protein
NP_009225.1:p.(Arg866His)
gnomAD AF
1.9831162440769895e-05 (v4.1)
ClinVar
Benign
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
Benign: BP1 Strong is supported by Arg866 being outside ENIGMA critical domains with SpliceAI 0.001.
2
Benign: BP5 Strong is supported by the exact clinical-history LR of 0.03014649625443013.
3
Benign: BP6 Supporting is supported by the exact-variant ClinVar expert-panel Benign classification.
Final determination: Under ENIGMA Table 3's conflicting-evidence point system, BP1 Strong (-4), BP5 Strong (-4), and BP6 Supporting (-1) total -9, which is within the Benign range of -7 or less.
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 N/A Not applicable: c.2597G>A is missense, p.(Arg866His), not an ENIGMA-defined null variant eligible for PVS1.
cspec vcep_specifications_v1_2_2024_11_18 vcep_specifications_table4_v1_2_2024_11_18
PS1 Not met Not met: no pathogenic or likely pathogenic same-codon comparator was identified; p.Arg866Cys is ENIGMA BS3 Strong/neutral and p.Arg866Gln is unclassified.
cspec vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 spliceai
PS2 N/A Not applicable: the ENIGMA BRCA1/2 specification explicitly designates PS2 as not applicable.
cspec
PS3 Not met Not met: ENIGMA records no aberrant splicing and provides no calibrated damaging protein assay or PS3 assignment for c.2597G>A (p.Arg866His).
cspec vcep_supplementarytables_v1_2_2024_11_18 vcep_specifications_table9_v1_2_2024_11_18 PMID:18273839
PS4 Not assessed Not assessed: no case-control OR, confidence interval, or p-value is available for the reported variant observations.
cspec
PM1 N/A Not applicable: ENIGMA explicitly excludes PM1, and Arg866 lies outside RING 2-101, coiled-coil 1391-1424, and BRCT 1650-1857.
cspec vcep_appendices_v1_2_2024_11_18
PM2 Not met Not met: the variant is observed at 4/236516 non-cancer exome alleles and 2/147936 non-cancer genome alleles, rather than absent from controls.
cspec gnomad_v2 gnomad_v4
PM3 Not assessed Not assessed: no affected-proband co-occurrence, phase, or Fanconi-anemia phenotype is documented to meet the ENIGMA PM3 requirements.
cspec vcep_specifications_v1_2_2024_11_18
PM4 N/A Not applicable: ENIGMA explicitly excludes PM4 for BRCA1, and p.(Arg866His) is a missense substitution without protein-length change.
cspec vcep_specifications_v1_2_2024_11_18
PM5 N/A Not applicable: ENIGMA PM5 is restricted to pathogenic protein-termination-codon comparators, whereas Arg866His is a missense substitution.
cspec pm5_candidates vcep_specifications_table4_v1_2_2024_11_18
PM6 N/A Not applicable: the ENIGMA BRCA1/2 specification explicitly designates PM6 as not applicable.
cspec
PP1 Not assessed Not assessed: no family segregation data or quantitative co-segregation LR is available to compare with the ENIGMA PP1 threshold of >=2.08:1.
cspec
PP2 N/A Not applicable: ENIGMA explicitly lists PP2 as Not Applicable for BRCA1/2, so no missense-mechanism PP2 evidence can be assigned.
cspec
PP3 Not met Not met: SpliceAI max delta 0.001 is below ENIGMA's >=0.2 splice-impact threshold, and the missense protein path also requires an in-domain change.
cspec vcep_supplementarytables_v1_2_2024_11_18 bayesdel spliceai PMID:18273839
PP4 Not met Not met: clinical-history LR 0.03014649625443013 >= 2.08? No, below the ENIGMA PP4 supporting threshold.
cspec PMID:31853058
PP5 Not met Not met: exact-variant ClinVar expert panel classification is Benign, not Pathogenic or Likely pathogenic.
clinvar
BA1 Not met Not met: non-cancer group-max FAF is 3.24e-06 in gnomAD v2.1 and 0 in gnomAD v3.1, below the 0.001 BA1 threshold.
cspec gnomad_v2 gnomad_v4
BS1 Not met Not met: the highest applicable non-cancer group-max FAF is 3.24e-06, below the 0.00002 threshold for BS1 Supporting.
cspec gnomad_v2 gnomad_v4
BS2 Not met Not met: gnomAD non-cancer datasets report zero homozygotes, providing no qualifying BS2 points for this BRCA1 variant.
cspec gnomad_v2 gnomad_v4
BS3 N/A Not applicable: c.2597G>A has mRNA-only minigene no-aberration evidence, which ENIGMA directs to BP7 rather than BS3.
cspec vcep_supplementarytables_v1_2_2024_11_18 vcep_specifications_table9_v1_2_2024_11_18 PMID:18273839
BS4 Not assessed Not assessed: no affected non-carrier relatives or quantitative non-segregation LR is available to compare with the ENIGMA BS4 threshold of <=0.48:1.
cspec
BP1 Met Met, Strong: Arg866 is outside all ENIGMA critical domains and SpliceAI max delta 0.001 is below the <=0.1 BP1 threshold.
cspec vcep_appendices_v1_2_2024_11_18 spliceai
BP2 N/A Not applicable: ENIGMA explicitly prohibits BP2 and permits related allelic evidence only through its BS2 framework.
cspec vcep_specifications_v1_2_2024_11_18
BP3 N/A Not applicable: ENIGMA explicitly excludes BP3 for BRCA1, and p.(Arg866His) is not an in-frame indel in a repetitive region.
cspec vcep_specifications_v1_2_2024_11_18
BP4 Not met Not met: p.Arg866His is outside ENIGMA's required clinically important domains despite BayesDel 0.145553 meeting the <=0.15 cutoff.
cspec vcep_supplementarytables_v1_2_2024_11_18 bayesdel spliceai PMID:18273839
BP5 Met Met, Strong: clinical-history LR 0.03014649625443013 <= 0.05? Yes, satisfying the ENIGMA BP5 Strong threshold.
cspec PMID:31853058
BP6 Met Met, Supporting: exact-variant ClinVar expert panel classification is Benign, satisfying the requested BP6 rule.
clinvar
BP7 N/A Not applicable: BRCA1 c.2597G>A is missense, whereas BP7 is restricted to synonymous variants.
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