LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-09-04
Case ID: NM_007294.4_c.2501G_A_20260904_155935
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
VUS
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
ClinVar
Uncertain significance
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
BP1 strong (met): p.Gly834Glu is a missense outside all clinically important BRCA1 domains (RING 2-101, coiled-coil 1391-1424, BRCT 1650-1857) with SpliceAI max delta 0.001, indicating no predicted splice impact.
Final determination: ENIGMA v1.2 Table 3 leaves the variant of Uncertain Significance because BP1 strong is the only applied criterion and a single aggregated benign-strong code does not satisfy any benign or likely-benign combination (lone Strong requires multiple evidence types; no supporting/moderate benign code or second Strong is present).
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.2501G>A is a missense (p.Gly834Glu), not a null variant, with no predicted splicing (SpliceAI max delta 0.001).
cspec spliceai PMID:26306726
PS1 Not met Not met: no pathogenic or likely pathogenic p.Gly834Glu exists in ClinVar (5 VUS, 1 likely benign, 1 benign), and only c.2501G>A can produce this amino acid change.
cspec clinvar spliceai vcep_specifications_v1_2_2024_11_18 PMID:26306726
PS2 N/A Not applicable: ENIGMA BRCA1/2 v1.2 disallows PS2 (no calibration for de novo occurrences in common BRCA-related cancer), and no de novo observation for c.2501G>A is reported.
cspec clinvar PMID:26306726
PS3 Not assessed PS3 not assessed: ENIGMA Table 9/ST4 hold no calibrated functional assay entry for c.2501G>A (0/4,730 and 0/4,304 rows), and no published assay exists.
cspec vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18
PS4 Not met Not met: ENIGMA PS4 requires case-control p ≤ 0.05 and OR ≥ 4 (lower CI excluding 2.0); only a single VUS case observation (PMID:26306726) exists, with no OR or p-value.
cspec PMID:26306726
PM1 N/A Not applicable: ENIGMA v1.2 does not use PM1 for BRCA1 (subsumed by PP3/BP4); Gly834 lies outside RING aa 2-101, coiled-coil aa 1391-1424, and BRCT aa 1650-1857.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
PM2 Not assessed Not assessed: ENIGMA PM2 (supporting) requires absence from gnomAD v2.1/v3.1 non-cancer controls, yet gnomAD data is unavailable and one submitter reports rs757383244 present at an unstated frequency.
cspec gnomad_canada clinvar vcep_supplementarytables_v1_2_2024_11_18
PM3 Not met Not met: ENIGMA v1.2 applies PM3 only to Fanconi-anemia phenotypes with co-occurrent same-gene variants; c.2501G>A has no second BRCA1 variant or phase data.
cspec PMID:26306726
PM4 N/A Not applicable: ENIGMA v1.2 does not use PM4, and a missense substitution cannot alter protein length.
cspec
PM5 N/A Not applicable: ENIGMA v1.2 applies PM5 only to protein-termination-codon variants (PM5_PTC) and does not use missense PM5; p.Gly834Glu is missense with no pathogenic codon-834 comparator.
cspec clinvar vcep_specifications_v1_2_2024_11_18 vcep_specifications_table4_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 PMID:26306726
PM6 N/A Not applicable: ENIGMA BRCA1/2 v1.2 disallows PM6 (assumed de novo uncalibrated in common BRCA-related cancer), and no assumed-de-novo observation for c.2501G>A is reported.
cspec clinvar PMID:26306726
PP1 Not assessed Not assessed: no pedigree or co-segregation LR for c.2501G>A; ENIGMA PP1 requires a quantitative segregation LR of at least 2.08:1 for supporting strength.
cspec clinvar PMID:26306726 PMID:25085752
PP2 N/A Not applicable: ENIGMA v1.2 does not use PP2 for BRCA1 because benign missense variation is common and missense is not a common pathogenic mechanism.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
PP3 Not met Not met: SpliceAI max delta 0.001 is far below the >=0.2 PP3 splice-impact threshold, and the BayesDel protein path does not apply to this out-of-domain missense.
cspec spliceai vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
PP4 Not assessed Not assessed: ENIGMA PP4 needs a combined clinical likelihood ratio ≥ 2.08, but c.2501G>A has no variant-level LR (absent from the Li 2020 BRCA1 clinical-history LR table).
cspec vcep_pmid_31853058_brca1_clinical_history_lr
PP5 N/A Not applicable: ENIGMA BRCA1/2 v1.2 does not use PP5, and ClinVar VCV000462587 has no exact-variant expert-panel Pathogenic/Likely pathogenic classification (0 expert-panel submissions).
cspec clinvar
BA1 Not assessed Not assessed: ENIGMA BA1 requires a gnomAD v2.1/v3.1 non-founder FAF above 0.1% (0.001), and no gnomAD allele-frequency value is available for this variant to test the threshold.
cspec gnomad_canada clinvar
BS1 Not assessed Not assessed: ENIGMA BS1 needs gnomAD v2.1/v3.1 non-founder FAF above 0.002% (supporting) or 0.01% (strong), but no gnomAD frequency value is available for this variant.
cspec gnomad_canada clinvar vcep_supplementarytables_v1_2_2024_11_18
BS2 Not assessed Not assessed: ENIGMA BS2 requires point-scored observations of biallelic (homozygous/in-trans) carriers without Fanconi anemia; no such observation exists for c.2501G>A.
cspec
BS3 Not assessed BS3 not assessed: no well-established functional study shows a benign effect for c.2501G>A; ENIGMA Table 9 and ST4 contain zero entries.
cspec vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18
BS4 Not assessed Not assessed: no non-segregation data or co-segregation LR for c.2501G>A; ENIGMA BS4 requires a segregation LR of at most 0.48:1 for supporting strength.
cspec clinvar PMID:26306726 PMID:25085752
BP1 Met Met (BP1_Strong): p.Gly834Glu is a missense outside all clinically important domains (RING 2-101, coiled-coil 1391-1424, BRCT 1650-1857) with SpliceAI max delta 0.001 <= 0.1.
cspec spliceai vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
BP2 N/A Not applicable: ENIGMA BRCA1/2 v1.2 declares BP2 not applicable (cis/trans evidence handled via BS2); no in-trans or in-cis pathogenic partner observed.
cspec
BP3 N/A Not applicable: ENIGMA v1.2 does not use BP3, and no in-frame indel in a repeat region is present.
cspec
BP4 Not met Not met: ENIGMA BP4 (BayesDel <=0.15 AND SpliceAI <=0.1) applies only to missense inside clinically important domains; Gly834 lies outside RING, coiled-coil and BRCT.
cspec spliceai vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
BP5 Not assessed Not assessed: ENIGMA BP5 needs a combined clinical likelihood ratio ≤ 0.48, but c.2501G>A has no variant-level LR (absent from the Li 2020 BRCA1 clinical-history LR table).
cspec vcep_pmid_31853058_brca1_clinical_history_lr
BP6 N/A Not applicable: ENIGMA BRCA1/2 v1.2 does not use BP6, and ClinVar VCV000462587 has no exact-variant expert-panel Benign/Likely benign classification (0 expert-panel submissions).
cspec clinvar
BP7 N/A Not applicable: BP7 is reserved for synonymous (silent) variants, and c.2501G>A is a missense variant (p.Gly834Glu).
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
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