LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-10-16
Case ID: NM_007294.4_c.3245C_T_20261016_142708
Framework: ACMG/AMP 2015 with ENIGMA Table 3 adaptations
Variant classification summary

NM_007294.4:c.3245C>T

BRCA1  · NP_009225.1:p.(Ala1082Val)  · NM_007294.4
GRCh37: chr17:41244303 G>A  ·  GRCh38: chr17:43092286 G>A
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.(Ala1082Val)
gnomAD AF
ClinVar
Uncertain significance
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
BP1 Strong met: Ala1082 is outside approved BRCA1 functional domains and SpliceAI is 0.008.
2
VUS: BP1 Strong alone lacks the multiple benign evidence types required for Likely Benign under ENIGMA Table 3.
Final determination: Under ENIGMA Table 3, one Strong benign criterion requires multiple benign evidence types for Likely Benign; with only BP1 Strong applied, the final call is VUS.
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.3245C>T is missense, p.(Ala1082Val), rather than an ENIGMA-defined nonsense, frameshift, splice-site, initiation-codon, or exon-deletion null variant.
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 0.008, but no previously pathogenic p.Ala1082 substitution was identified for the required same-amino-acid comparison.
cspec vcep_specifications_v1_2_2024_11_18 spliceai
PS2 N/A Not applicable: ENIGMA prohibits PS2 because de novo occurrence predictive value is uncalibrated for common BRCA1/2-related cancers.
cspec
PS3 Not assessed Not assessed: no variant-level PS3 recommendation or functional assay result was found for c.3245C>T/p.Ala1082Val in the governing VCEP sources.
cspec vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001
PS4 Not assessed Not assessed: no variant-specific case-control odds ratio, p-value, or confidence interval was available to evaluate the ENIGMA PS4 thresholds.
cspec clinvar
PM1 N/A Not applicable: ENIGMA says PM1 is not used, and residue Ala1082 lies outside RING 2-101, coiled-coil 1391-1424, and BRCT 1650-1857.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
PM2 Not assessed Not assessed: the variant is absent from both specified non-cancer gnomAD datasets, but the required regional average read depth of at least 25 is not reported.
cspec gnomad_v2 gnomad_v4
PM3 Not assessed Not assessed: no documented same-gene pathogenic/likely pathogenic variant in trans or Fanconi-anemia phenotype is available for point assignment.
cspec
PM4 N/A Not applicable: p.(Ala1082Val) is a missense substitution with no protein-length change, while ENIGMA PM4 covers in-frame indels or stop-loss variants and says not to use it.
vcep_specifications_v1_2_2024_11_18 cspec
PM5 N/A Not applicable: ENIGMA repurposes PM5 for PVS1-eligible protein-termination variants, whereas c.3245C>T is a missense substitution.
cspec vcep_specifications_table4_v1_2_2024_11_18 vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
PM6 N/A Not applicable: ENIGMA prohibits PM6 because de novo occurrence predictive value is uncalibrated for common BRCA1/2-related cancers.
cspec
PP1 Not assessed Not assessed: no variant-specific segregation LR or affected-relative data were available, and the governing multifactorial table contained no c.3245C>T entry.
cspec vcep_humu_40_1557_s001
PP2 N/A Not applicable: ENIGMA explicitly says not to use PP2 because BRCA1 has a high frequency of benign missense variants.
cspec vcep_specifications_v1_2_2024_11_18
PP3 Not met Not met: REVEL 0.481 is below the >=0.644 supporting PP3 threshold for missense variants.
cspec revel vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
PP4 Not assessed Not assessed: no combined multifactorial likelihood ratio was available for comparison with the PP4 supporting threshold of >=2.08:1.
cspec vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058 PMID:17924331
PP5 N/A Not applicable: ENIGMA says not to use PP5, and the exact ClinVar record has zero expert-panel submissions.
cspec clinvar
BA1 Not met Not met: the variant is absent from the specified non-cancer gnomAD datasets, so its filter allele frequency does not exceed the 0.001 BA1 threshold.
cspec gnomad_v2 gnomad_v4
BS1 Not met Not met: absence from the specified non-cancer gnomAD datasets provides no filter allele frequency above 0.00002, the minimum BS1 threshold.
cspec gnomad_v2 gnomad_v4
BS2 Not assessed Not assessed: no qualifying proband-level phase, homozygote, age/follow-up, cancer-status, or Fanconi Anemia data are available for the BS2 point system.
cspec
BS3 Not assessed Not assessed: no variant-level BS3 recommendation or functional assay result was found for c.3245C>T/p.Ala1082Val in the governing VCEP sources.
cspec vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001
BS4 Not assessed Not assessed: no variant-specific non-segregation LR or family genotype data were available, and the governing multifactorial table contained no c.3245C>T entry.
cspec vcep_humu_40_1557_s001
BP1 Met Met at strong: Ala1082 is outside all approved BRCA1 domains and SpliceAI max delta 0.008 is below the ENIGMA <=0.1 threshold.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 spliceai
BP2 N/A Not applicable: ENIGMA BRCA1 V1.2 explicitly excludes BP2 and permits it only in the context of BS2.
cspec
BP3 N/A Not applicable: p.(Ala1082Val) is missense, not an in-frame insertion/deletion in a repetitive nonfunctional region, and ENIGMA explicitly says BP3 is not used.
vcep_specifications_v1_2_2024_11_18 cspec
BP4 Not met Not met: REVEL 0.481 is above the <=0.29 supporting BP4 threshold for missense variants.
cspec revel vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
BP5 Not assessed Not assessed: no combined multifactorial likelihood ratio was available to test against the BP5 supporting inequality LR <=0.48:1.
cspec vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058 PMID:17924331
BP6 N/A Not applicable: ENIGMA says not to use BP6, and no exact-variant ClinVar expert-panel benign classification exists.
cspec clinvar
BP7 N/A Not applicable: c.3245C>T is missense, whereas BP7 applies only to synonymous or qualifying intronic variants.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
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