LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-05-06
Case ID: NM_007294.3_c.4159T_C_20260506_194008
Framework: ACMG/AMP 2015 with ENIGMA Table 3 adaptations
Variant classification summary

NM_007294.3:c.4159T>C

BRCA1  · NP_009225.1:p.(Ser1387Pro)  · NM_007294.3
GRCh37: chr17:41242987 A>G  ·  GRCh38: chr17:43090970 A>G
Gene: BRCA1 Transcript: NM_007294.3
Final call
Likely Benign
BP1_Strong BP6_Supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
BRCA1
Transcript
NM_007294.3
Protein
NP_009225.1:p.(Ser1387Pro)
gnomAD AF
ClinVar
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
The BRCA1 c.4159T>C (p.Ser1387Pro) variant has been reported in ClinVar, where the ClinGen ENIGMA BRCA1/2 expert panel classifies it as Likely Benign despite conflicting individual submissions.
2
This variant is present at very low frequency in population databases, including gnomAD v2.1 at 1/248290 alleles (AF 0.00040%) and gnomAD v4.1 at 2/1612348 alleles (AF 0.00012%; grpmax FAF 2.8e-07), which is too low for BA1 or BS1 and means PM2 is not met because the variant is not absent from controls.
3
No exact curated functional assay result for p.(Ser1387Pro) was identified in the ENIGMA BRCA1 functional tables, so PS3 and BS3 were not applied from the available functional evidence.
4
In silico data support a benign interpretation under the ENIGMA BRCA1 framework because p.(Ser1387Pro) lies outside the BRCA1 clinically important domains, SpliceAI predicts no splice impact (max delta 0.00), and the missense change therefore meets BP1_Strong; BayesDel is 0.148379 and PP3 is not met.
Final determination: Likely benign is supported by one strong benign criterion and one supporting benign criterion (BP1_Strong plus BP6_Supporting) under ENIGMA Table 3.
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 This variant is a missense substitution, p.(Ser1387Pro), and does not fall into the BRCA1 null-variant or canonical splice categories used for PVS1. Available splice prediction does not indicate an RNA effect that would support RNA-based PVS1 application.
cspec pvs1_gene_context pvs1_variant_assessment spliceai
PS1 Not assessed No evidence was identified showing that this variant produces the same protein change as a previously established pathogenic or likely pathogenic BRCA1 variant, and no matched splice mechanism was identified.
cspec clinvar
PS2 N/A This framework does not use PS2 for BRCA1 variant classification.
cspec
PS3 Not assessed No calibrated variant-specific functional study supporting a damaging effect was identified for p.(Ser1387Pro) in the ENIGMA BRCA1 curated functional assay tables, so PS3 was not applied.
vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 cspec
PS4 Not assessed Available evidence does not show a case-control enrichment study or other quantitative affected-versus-control analysis meeting ENIGMA BRCA1 PS4 requirements for this variant.
cspec clinvar
PM1 N/A The ENIGMA BRCA1 framework does not use PM1 for BRCA1 variant classification.
cspec
PM2 Not met This variant is not absent from population databases. It is present in gnomAD v2.1 at 1/248290 alleles (AF 0.00040%) and in gnomAD v4.1 at 2/1612348 alleles (AF 0.00012%), so ENIGMA BRCA1 PM2_Supporting is not met.
cspec gnomad_v2 gnomad_v4
PM3 Not assessed No evidence was identified showing this variant in the biallelic Fanconi anemia context required for ENIGMA BRCA1 PM3 scoring.
cspec
PM4 N/A This framework does not use PM4 for BRCA1 variant classification.
cspec
PM5 N/A In the ENIGMA BRCA1 framework, PM5 is used as PM5_PTC for protein-truncating variants. This variant is a missense substitution and is not eligible for PM5_PTC.
cspec vcep_specifications_table4_v1_2_2024_11_18
PM6 N/A This framework does not use PM6 for BRCA1 variant classification.
cspec
PP1 Not assessed No quantitative co-segregation data were identified for this variant, so PP1 was not applied.
cspec clinvar
PP2 N/A This framework does not use PP2 for BRCA1 variant classification.
cspec
PP3 Not met ENIGMA BRCA1 PP3 for missense variants requires location in a clinically important functional domain with BayesDel no-AF score at least 0.28, or predicted splice impact with SpliceAI at least 0.2. p.(Ser1387Pro) lies outside the BRCA1 RING (aa 2-101), coiled-coil (aa 1391-1424), and BRCT (aa 1650-1857) domains; BayesDel is 0.148379, SpliceAI max delta is 0.00, and REVEL is 0.481, so PP3 is not met.
cspec bayesdel spliceai revel
PP4 Not met The BRCA1 clinical-history likelihood ratio for this variant is 0.645 in 1 proband, which is below the ENIGMA PP4 threshold of 2.08 and falls in the neutral zone, so PP4 is not met.
cspec vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058
PP5 N/A This framework does not use PP5 for BRCA1 variant classification.
cspec
BA1 Not met The highest observed gnomAD v4.1 filter allele frequency is 2.8e-07, which is far below the ENIGMA BRCA1 BA1 threshold of 0.001, so BA1 is not met.
cspec gnomad_v4
BS1 Not met The highest observed gnomAD v4.1 filter allele frequency is 2.8e-07, which is below the ENIGMA BRCA1 BS1 thresholds of greater than 0.00002 for BS1_Supporting and greater than 0.0001 for BS1, so BS1 is not met.
cspec gnomad_v4
BS2 Not assessed No evidence was identified showing this variant in the unaffected or non-Fanconi-anemia context required for ENIGMA BRCA1 BS2 point assignment.
cspec
BS3 Not assessed No calibrated variant-specific functional study showing no damaging effect was identified for p.(Ser1387Pro) in the ENIGMA BRCA1 curated functional assay tables, so BS3 was not applied.
vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 cspec
BS4 Not assessed No quantitative lack-of-segregation data were identified for this variant, so BS4 was not applied.
cspec clinvar
BP1 Met p.(Ser1387Pro) is a missense variant outside the ENIGMA BRCA1 clinically important domains, and SpliceAI predicts no splice impact with a max delta score of 0.00, which is below the BP1_Strong threshold of 0.1. This meets ENIGMA BRCA1 BP1_Strong.
cspec spliceai
BP2 N/A This framework does not use BP2 for BRCA1 variant classification.
cspec
BP3 N/A This framework does not use BP3 for BRCA1 variant classification.
cspec
BP4 N/A Although BayesDel is 0.148379 and SpliceAI max delta is 0.00, ENIGMA BRCA1 restricts missense BP4 to variants inside clinically important functional domains. p.(Ser1387Pro) lies outside those domains, so BP4 is not applicable and benign computational evidence is captured by BP1_Strong instead.
cspec bayesdel spliceai
BP5 Not met The BRCA1 clinical-history likelihood ratio for this variant is 0.645 in 1 proband, which is above the ENIGMA BP5 threshold of 0.48 and falls in the neutral zone, so BP5 is not met.
cspec vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058
BP6 Met Expert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Likely benign.
cspec clinvar
BP7 Not assessed No RNA study showing a normal transcript profile was identified for this variant, so BP7 was not applied.
cspec spliceai vcep_supplementarytables_v1_2_2024_11_18
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