LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-10-08
Case ID: NM_007294.4_c.2927A_G_20261008_151858
Framework: ACMG/AMP 2015 with ENIGMA Table 3 adaptations
Variant classification summary

NM_007294.4:c.2927A>G

BRCA1  · NP_009225.1:p.(Asn976Ser)  · NM_007294.4
GRCh37: chr17:41244621 T>C  ·  GRCh38: chr17:43092604 T>C
Gene: BRCA1 Transcript: NM_007294.4
Final call
Likely Benign
PM2 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.(Asn976Ser)
gnomAD AF
ClinVar
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
PM2 supporting: the variant is absent from the preferred non-cancer gnomAD exome and genome datasets.
2
BP1 strong: residue 976 lies outside ENIGMA BRCA1 functional domains and SpliceAI maximum delta is 0.004.
Final determination: Under the ENIGMA BRCA1 Version 1.2 conflicting-evidence point system, PM2 Supporting contributes +1 and BP1 Strong contributes -4, giving -3, which maps to 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 N/A Not applicable: c.2927A>G produces missense p.Asn976Ser with no premature termination, unchanged protein length, and no PVS1 null-variant consequence.
cspec vcep_specifications_table4_v1_2_2024_11_18 vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
PS1 Not assessed Not assessed: SpliceAI max delta is 0.004, but no qualifying previously pathogenic alternate producing p.Asn976Ser was identified.
cspec vcep_specifications_v1_2_2024_11_18 clinvar spliceai pm5_candidates
PS2 N/A Not applicable: ENIGMA v1.2 explicitly prohibits PS2 because de novo observations lack calibrated predictive value for relatively common BRCA1/2-related cancers.
cspec vcep_specifications_v1_2_2024_11_18
PS3 Not assessed Not assessed: no variant-specific calibrated damaging functional assay result or ENIGMA PS3 assignment was found for c.2927A>G.
cspec vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_humu_40_1557_s001
PS4 Not assessed Not assessed: no variant-specific PS4 case-control odds ratio, confidence interval, or p-value was available for comparison with OR >=4 and p-value <=0.05.
cspec
PM1 N/A Not applicable: ENIGMA marks PM1 N/A, and residue 976 lies outside BRCA1 RING 2-101, coiled-coil 1391-1424, and BRCT 1650-1857 domains.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
PM2 Met Met at supporting: the variant is absent from the preferred non-cancer gnomAD exome and genome datasets required by the ENIGMA PM2 rule.
cspec gnomad_v2 gnomad_v4
PM3 Not assessed Not assessed: no Fanconi-anemia phenotype, second BRCA1 pathogenic allele, or phase observation is documented for PM3 point assignment.
cspec
PM4 N/A Not applicable: PM4 is not used by ENIGMA, and p.Asn976Ser is a missense substitution with no in-frame length change or stop-loss event.
cspec vcep_specifications_v1_2_2024_11_18
PM5 N/A Not applicable: ENIGMA repurposes PM5 for PVS1-eligible PTC variants, whereas c.2927A>G is a missense substitution.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_specifications_table4_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 pm5_candidates
PM6 N/A Not applicable: ENIGMA v1.2 explicitly prohibits PM6 because de novo observations lack calibrated predictive value for relatively common BRCA1/2-related cancers.
cspec vcep_specifications_v1_2_2024_11_18
PP1 Not assessed Not assessed: no variant-specific affected-family genotypes, meioses, or quantitative co-segregation LR were provided to compare with the PP1 threshold of 2.08:1.
cspec vcep_specifications_v1_2_2024_11_18
PP2 N/A Not applicable: ENIGMA excludes PP2 because missense variants are not a common pathogenicity mechanism for BRCA1.
cspec vcep_specifications_v1_2_2024_11_18
PP3 Not met Not met: REVEL 0.396 is below the 0.644 supporting PP3 threshold, and the ENIGMA BayesDel score -0.187387 is below 0.28.
cspec revel bayesdel
PP4 Not assessed Not assessed: no variant-specific combined clinical likelihood ratio was available for comparison with the PP4 Supporting threshold LR >=2.08.
cspec PMID:31853058 PMID:17924331
PP5 Not met Not met: ClinVar reported zero expert-panel submissions for c.2927A>G, so the required exact-variant Pathogenic or Likely pathogenic trigger is absent.
cspec
BA1 Not met Not met: the variant is absent from the governing non-cancer gnomAD datasets, so its filter allele frequency does not exceed the ENIGMA BA1 threshold of 0.001.
cspec gnomad_v2 gnomad_v4
BS1 Not met Not met: the variant is absent from the preferred non-cancer gnomAD datasets, so no filter allele frequency exceeds the ENIGMA BS1 threshold of 0.0001.
cspec gnomad_v2 gnomad_v4
BS2 Not assessed Not assessed: no qualifying healthy-adult clinical observation or ENIGMA BS2 point data are available for this variant, and gnomAD frequency data cannot substitute for BS2.
cspec gnomad_v2 gnomad_v4
BS3 Not assessed Not assessed: no variant-specific calibrated benign functional assay result or ENIGMA BS3 assignment was found for c.2927A>G.
cspec vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_humu_40_1557_s001
BS4 Not assessed Not assessed: no variant-specific non-segregating affected relatives, meioses, or quantitative LR were provided to compare with the BS4 threshold of ≤0.48:1.
cspec vcep_specifications_v1_2_2024_11_18
BP1 Met Met, Strong: residue 976 is outside approved BRCA1 domains and SpliceAI max delta 0.004 is below the <=0.1 BP1 threshold.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 spliceai
BP2 N/A Not applicable: the ENIGMA BRCA1/2 specification explicitly says BP2 is not used and limits it to the BS2 context.
cspec
BP3 N/A Not applicable: BP3 is not used by ENIGMA, and this variant is a missense substitution rather than an in-frame insertion or deletion in a repeat region.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
BP4 Not met Not met: REVEL 0.396 exceeds the <=0.29 supporting BP4 threshold and remains in the gray zone for benign protein impact.
cspec revel bayesdel
BP5 Not assessed Not assessed: no variant-specific combined LR was available to test the BP5 Supporting inequality LR <=0.48 and >0.23.
cspec PMID:31853058 PMID:17924331
BP6 Not met Not met: ClinVar reported zero expert-panel submissions for c.2927A>G, so the required exact-variant Benign or Likely benign trigger is absent.
cspec
BP7 N/A Not applicable: c.2927A>G is missense, p.Asn976Ser, whereas BP7 is restricted to synonymous variants.
cspec
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