LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-10-25
Case ID: NM_007294.4_c.686C_T_20261025_221525
Framework: ACMG/AMP 2015 with ENIGMA Table 3 adaptations
Variant classification summary

NM_007294.4:c.686C>T

BRCA1  · NP_009225.1:p.(Ser229Phe)  · NM_007294.4
GRCh37: chr17:41246862 G>A  ·  GRCh38: chr17:43094845 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.(Ser229Phe)
gnomAD AF
ClinVar
Uncertain significance
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
VUS: BP1 Strong applies because p.Ser229Phe is outside ENIGMA-defined functional domains and SpliceAI maximum delta is 0.045.
Final determination: ENIGMA Table 3 requires additional benign evidence for a Strong benign criterion to support Likely Benign; with BP1 Strong alone and no pathogenic combination, the result 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.686C>T is a missense substitution, whereas the VCEP PVS1 rule is limited to 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: no previously classified pathogenic variant with the same p.Ser229Phe amino-acid change was identified, despite SpliceAI max delta 0.045.
cspec
PS2 N/A Not applicable: the VCEP prohibits PS2 because BRCA1/2 cancers are relatively common and de novo predictive capacity is uncalibrated.
cspec
PS3 Not assessed Not assessed: ENIGMA Table 9 and supplementary ST4 contain no matching c.686C>T, p.Ser229Phe, or p.S229F functional-assay entry.
cspec vcep_specifications_v1_2_2024_11_18 vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_humu_40_1557_s001
PS4 Not assessed Not assessed: no qualifying matched case-control p-value, OR, or confidence interval is available for c.686C>T.
cspec vcep_specifications_v1_2_2024_11_18
PM1 N/A Not applicable: ENIGMA explicitly says PM1 is not used, regardless of residue 229 being outside its listed critical domains.
cspec
PM2 Not assessed Not assessed: the variant is absent from both specified gnomAD datasets, but the required regional average read depth >=25 is unavailable.
cspec gnomad_v2 gnomad_v4 vcep_appendices_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001
PM3 Not assessed Not assessed: no Fanconi Anemia phenotype, co-occurring BRCA1 pathogenic variant, affected proband, or phase information is available for PM3 point assignment.
vcep_specifications_v1_2_2024_11_18
PM4 N/A Not applicable: p.(Ser229Phe) is a missense substitution with no protein-length change, and the VCEP directs that PM4 is not used.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
PM5 N/A Not applicable: ENIGMA reserves PM5 for pathogenic PTC comparisons, whereas this variant is missense p.Ser229Phe.
cspec
PM6 N/A Not applicable: the VCEP prohibits PM6 because BRCA1/2 cancers are relatively common and de novo predictive capacity is uncalibrated.
cspec
PP1 Not assessed Not assessed: no affected-relative genotypes or quantitative co-segregation LR are available to compare with the VCEP PP1 supporting threshold of LR ≥2.08:1.
cspec
PP2 N/A Not applicable: ENIGMA says PP2 is not used because BRCA1 has a high frequency of benign missense variants.
cspec
PP3 Not met Not met: SpliceAI maximum delta 0.045 is below the ENIGMA PP3 splicing threshold of 0.2, and BayesDel 0.247749 is below the 0.28 protein-impact threshold.
cspec spliceai bayesdel
PP4 Not assessed Not assessed: the governing clinical-history table has no c.686C>T row and no combined clinical LR is available.
cspec vcep_specifications_v1_2_2024_11_18 vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058
PP5 N/A Not applicable: the ENIGMA BRCA1 specification explicitly states that PP5 should not be used.
cspec vcep_specifications_v1_2_2024_11_18
BA1 Not met Not met: the variant is absent from both specified non-cancer gnomAD datasets, so no filter allele frequency above 0.001 is available for BA1.
cspec gnomad_v2 gnomad_v4 vcep_appendices_v1_2_2024_11_18
BS1 Not met Not met: the variant is absent from both specified non-cancer gnomAD datasets, so no FAF above 0.00002 supports BS1.
cspec gnomad_v2 gnomad_v4 vcep_appendices_v1_2_2024_11_18
BS2 Not assessed Not assessed: no phenotyped cohort observation, homozygote, phase, or age/follow-up evidence is available for the BS2 point system.
cspec vcep_appendices_v1_2_2024_11_18
BS3 Not assessed Not assessed: ENIGMA Table 9 and supplementary ST4 contain no matching c.686C>T, p.Ser229Phe, or p.S229F functional-assay entry.
cspec vcep_specifications_v1_2_2024_11_18 vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_humu_40_1557_s001
BS4 Not assessed Not assessed: no non-segregation observations or quantitative co-segregation LR are available to compare with the VCEP BS4 supporting threshold of LR ≤0.48:1.
cspec
BP1 Met Met at strong: p.Ser229Phe lies outside ENIGMA domains and SpliceAI max delta 0.045 meets the ≤0.1 no-splicing threshold.
cspec
BP2 N/A Not applicable: the ENIGMA specification says BP2 is not to be used and applies it only in the context of BS2.
vcep_specifications_v1_2_2024_11_18
BP3 N/A Not applicable: p.(Ser229Phe) is not an in-frame deletion or insertion, the only variant type named by the VCEP BP3 rule.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
BP4 N/A Not applicable: p.Ser229Phe is a missense variant at residue 229, outside all ENIGMA-defined BRCA1 functional domains required for the BP4 missense path.
cspec
BP5 Not assessed Not assessed: no variant-specific combined LR is available to compare with the BP5 ≤0.48 threshold.
cspec vcep_specifications_v1_2_2024_11_18 vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058
BP6 N/A Not applicable: the ENIGMA BRCA1 specification explicitly states that BP6 should not be used.
cspec vcep_specifications_v1_2_2024_11_18
BP7 N/A Not applicable: BP7 covers silent or qualifying intronic variants, whereas c.686C>T produces the missense substitution p.Ser229Phe.
cspec
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