LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-10-02
Case ID: NM_007294.4_c.3800T_C_20261002_132558
Framework: ACMG/AMP 2015 with ENIGMA Table 3 adaptations
Variant classification summary

NM_007294.4:c.3800T>C

BRCA1  · NP_009225.1:p.(Leu1267Ser)  · NM_007294.4
GRCh37: chr17:41243748 A>G  ·  GRCh38: chr17:43091731 A>G
Gene: BRCA1 Transcript: NM_007294.4
Final call
Benign
BS3 strong BP1 strong BP5 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
BRCA1
Transcript
NM_007294.4
Protein
NP_009225.1:p.(Leu1267Ser)
gnomAD AF
5.575855800934514e-06 (v4.1)
ClinVar
Uncertain significance
OncoKB
Likely Neutral
Classification rationale
Interpretation summary
Generated evidence synthesis
1
BS3 strong: calibrated functional testing found c.3800T>C p.(Leu1267Ser) function similar to benign controls.
2
BP1 strong: p.Leu1267Ser lies outside ENIGMA BRCA1 functional domains and SpliceAI maximum delta is 0.034.
3
BP5 supporting: exact-variant clinical-history LR 0.2734782711138511 falls within the ENIGMA benign-supporting range.
Final determination: Under the ENIGMA BRCA1 Version 1.2 Table 3 framework, two Strong benign criteria satisfy the Benign combination rule; BS3 and BP1 therefore establish a Benign call, reinforced by BP5 Supporting.
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.3800T>C is a missense substitution, whereas ENIGMA PVS1 is restricted to qualifying loss-of-function null variants.
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 met Not met: SpliceAI max delta 0.034 qualifies, but no pathogenic or likely pathogenic alternate substitution at Leu1267 was found in the governing VCEP files.
cspec PMID:23867111 PMID:31911673
PS2 N/A Not applicable: ENIGMA prohibits PS2 because de novo occurrences lack calibrated predictive capacity for commonly occurring BRCA1/2-related cancers.
cspec vcep_specifications_v1_2_2024_11_18
PS3 Not met Not met: ENIGMA Table 9 reports protein function similar to benign controls and assigns BS3 Strong, not PS3, for c.3800T>C.
vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 vcep_specifications_v1_2_2024_11_18 PMID:23867111
PS4 Not assessed Not assessed: no exact-variant case-control p-value, odds ratio, or confidence interval was available to test the PS4 requirements.
cspec vcep_specifications_v1_2_2024_11_18
PM1 N/A Not applicable: ENIGMA does not use PM1, and residue 1267 lies outside BRCA1 RING 2-101, coiled-coil 1391-1424, and BRCT 1650-1857 domains.
cspec
PM2 Not met Not met: gnomAD v3.1 non-cancer contains 1 allele (AF 6.75794e-06), violating the VCEP requirement for absence from both required datasets.
cspec gnomad_v4 vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001
PM3 Not assessed Not assessed: ENIGMA PM3 requires Fanconi-anemia phenotype plus same-gene pathogenic co-occurrence; no affected-proband, phase, or Fanconi-anemia evidence is documented.
cspec
PM4 N/A Not applicable: p.(Leu1267Ser) changes one amino acid without the in-frame insertion, deletion, or stop-loss protein-length change required for PM4.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_specifications_table4_v1_2_2024_11_18
PM5 N/A Not applicable: ENIGMA excludes classic missense PM5, while its repurposed PM5 rule applies only to protein-termination-codon variants.
cspec
PM6 N/A Not applicable: ENIGMA prohibits PM6 because de novo occurrences lack calibrated predictive capacity for commonly occurring BRCA1/2-related cancers.
cspec vcep_specifications_v1_2_2024_11_18
PP1 Not assessed Not assessed: the exact variant row has no segregation LR, while the available clinical-history LR is 0.2734782711138511 and is not a co-segregation measure.
cspec vcep_humu_40_1557_s001 vcep_pmid_31853058_brca1_clinical_history_lr PMID:31131967
PP2 N/A Not applicable: ENIGMA marks PP2 as do not use because BRCA1 has a high frequency of benign missense variants.
cspec
PP3 Not met Not met: missense REVEL score 0.513 is below the 0.644 supporting PP3 threshold, and p.Leu1267Ser lies outside ENIGMA BRCA1 functional domains.
cspec revel vcep_appendices_v1_2_2024_11_18 vcep_specifications_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18
PP4 Not met Not met: clinical-history LR 0.2734782711138511 >= 2.08? no, so it does not meet the ENIGMA PP4 supporting threshold.
cspec vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058
PP5 Not met Not met: exact-match ClinVar record 142031 has 0 expert-panel submissions and no Pathogenic or Likely pathogenic expert-panel classification.
clinvar cspec
BA1 Not met Not met: maximum gnomAD filter allele frequency is 3.59e-06, far below the ENIGMA BA1 threshold of >0.001.
cspec gnomad_v4
BS1 Not met Not met: maximum gnomAD filter allele frequency is 3.59e-06, below the ENIGMA BS1_Supporting lower threshold of >0.00002.
cspec gnomad_v4
BS2 Not assessed Not assessed: gnomAD shows 0 homozygotes, and no qualifying phenotyped healthy individual or phase-specific cohort observation is available.
cspec gnomad_v4
BS3 Met Met, Strong: ENIGMA Table 9 pre-assigns BS3 Strong because calibrated testing found protein function similar to benign controls.
vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 vcep_specifications_v1_2_2024_11_18 PMID:23867111
BS4 Not assessed Not assessed: the exact variant row has no segregation LR, and the available clinical-history LR 0.2734782711138511 is not evidence of non-segregation.
cspec vcep_humu_40_1557_s001 vcep_pmid_31853058_brca1_clinical_history_lr PMID:31131967
BP1 Met Met, strong: residue 1267 is outside approved domains and SpliceAI max delta 0.034 is below the ENIGMA BP1 threshold of 0.1.
cspec PMID:31911673
BP2 N/A Not applicable: ENIGMA explicitly prohibits BP2 for BRCA1 and limits its use to the BS2 context.
cspec
BP3 N/A Not applicable: p.(Leu1267Ser) is a missense substitution, whereas ENIGMA BP3 is not used and concerns in-frame indels in nonfunctional repetitive regions.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
BP4 Not met Not met: missense REVEL score 0.513 exceeds the 0.29 supporting BP4 threshold and is indeterminate, with p.Leu1267Ser outside ENIGMA BRCA1 domains.
cspec revel vcep_appendices_v1_2_2024_11_18 vcep_specifications_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18
BP5 Met Met, supporting: clinical-history LR 0.2734782711138511 <= 0.48? yes, and >0.23, matching the ENIGMA BP5 supporting range.
cspec vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058
BP6 Not met Not met: exact-match ClinVar record 142031 has 0 expert-panel submissions, so laboratory Likely benign assertions cannot trigger BP6.
clinvar cspec
BP7 N/A Not applicable: c.3800T>C is a missense variant producing p.Leu1267Ser, whereas BP7 is restricted to synonymous or qualifying intronic variants.
cspec vcep_appendices_v1_2_2024_11_18 vcep_specifications_v1_2_2024_11_18
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