LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-11-02
Case ID: NM_007294.4_c.4683C_G_20261102_141302
Framework: ACMG/AMP 2015 with ENIGMA Table 3 adaptations
Variant classification summary

NM_007294.4:c.4683C>G

BRCA1  · NP_009225.1:p.(Thr1561=)  · NM_007294.4
GRCh37: chr17:41223248 G>C  ·  GRCh38: chr17:43071231 G>C
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.(Thr1561=)
gnomAD AF
ClinVar
Likely benign
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
BP1 Strong supports benignity because the silent variant lies outside the defined functional domains and has SpliceAI maximum delta 0.015.
Final determination: ENIGMA Table 3 does not permit Likely Benign from BP1 Strong alone without multiple benign evidence types; with no other met criterion, 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.4683C>G is synonymous (p.Thr1561=), whereas ENIGMA PVS1 applies to null variants; SpliceAI maximum delta is 0.015.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_specifications_table4_v1_2_2024_11_18 spliceai
PS1 Not assessed Not assessed: the synonymous variant has SpliceAI max delta 0.015, but no qualifying pathogenic comparator with a matching VCEP-defined splicing event is available.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 vcep_specifications_table4_v1_2_2024_11_18
PS2 N/A Not applicable: ENIGMA says de novo evidence is not calibrated for relatively common BRCA1/2-related cancers, regardless of parental testing.
cspec
PS3 Not assessed Not assessed: no calibrated damaging functional-assay result or pre-assigned PS3 strength was found for exact variant c.4683C>G.
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 matched case-control counts, odds ratio, confidence interval, p-value, or case-control likelihood ratio were available for c.4683C>G.
cspec vcep_specifications_v1_2_2024_11_18 PMID:12692171
PM1 N/A Not applicable: ENIGMA explicitly says PM1 is not used, and residue 1561 lies outside its RING, coiled-coil, and BRCT domains.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
PM2 Not assessed Not assessed: the variant was absent from both required non-cancer gnomAD datasets, but the VCEP-required regional average read depth of at least 25 was not reported.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 gnomad_v2 gnomad_v4
PM3 Not assessed Not assessed: no qualifying Fanconi Anemia phenotype, same-gene co-occurring pathogenic variant, or affected-proband phase evidence is documented.
cspec vcep_specifications_v1_2_2024_11_18
PM4 N/A Not applicable: the variant is synonymous and causes no protein-length change, while ENIGMA PM4 is restricted to in-frame indels or stop-loss variants and says do not use.
cspec vcep_specifications_v1_2_2024_11_18
PM5 N/A Not applicable: classic missense PM5 is not used by ENIGMA, and the synonymous variant is not a PVS1-eligible protein termination codon.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 vcep_specifications_table4_v1_2_2024_11_18
PM6 N/A Not applicable: ENIGMA says assumed de novo evidence is not calibrated for relatively common BRCA1/2-related cancers.
cspec
PP1 Not assessed Not assessed: no quantitative affected-family co-segregation likelihood ratio is available to compare with the ENIGMA PP1 threshold of LR >=2.08:1.
cspec
PP2 N/A Not applicable: ENIGMA does not use PP2 because missense variants are not a common BRCA1 pathogenicity mechanism, and this variant is synonymous.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
PP3 Not met Not met: SpliceAI maximum delta 0.015 is below the ENIGMA PP3 threshold of ≥0.2 for predicted splicing in silent variants.
cspec spliceai vcep_supplementarytables_v1_2_2024_11_18 vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_pmid_22505045_houdayer_2012_hummutat
PP4 Not assessed Not assessed: no variant-specific or combined multifactorial clinical likelihood ratio was available for comparison with the PP4 thresholds.
cspec vcep_specifications_v1_2_2024_11_18 vcep_pmid_31853058_brca1_clinical_history_lr
PP5 N/A Not applicable: the ENIGMA BRCA1 VCEP explicitly says PP5 is not for use.
cspec vcep_specifications_v1_2_2024_11_18
BA1 Not met Not met: the variant was absent from gnomAD v2.1 and v3.1 non-cancer datasets, so no filter allele frequency exceeded the VCEP's 0.001 BA1 threshold.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 gnomad_v2 gnomad_v4
BS1 Not met Not met: the variant was absent from gnomAD v2.1 and v3.1 non-cancer datasets, providing no filter allele frequency above the VCEP's 0.00002 BS1 lower threshold.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 gnomad_v2 gnomad_v4
BS2 Not assessed Not assessed: no qualifying phenotyped cohort observation, homozygote, or same-gene pathogenic-variant co-occurrence was available to assign the VCEP's BS2 points.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
BS3 Not assessed Not assessed: no calibrated benign functional-assay result or pre-assigned BS3 strength was found for exact variant c.4683C>G.
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 quantitative non-segregation likelihood ratio is available to compare with the ENIGMA BS4 supporting threshold of LR <=0.48:1.
cspec
BP1 Met Met at Strong: silent variant outside all VCEP-defined domains with SpliceAI max delta 0.015, below the required ≤0.1 no-splicing threshold.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
BP2 N/A Not applicable: the VCEP explicitly says BP2 is not used and limits it to the BS2 context.
cspec vcep_specifications_v1_2_2024_11_18
BP3 N/A Not applicable: c.4683C>G is a synonymous substitution, not an in-frame deletion or insertion in a repetitive region, and ENIGMA BP3 says do not use.
cspec vcep_specifications_v1_2_2024_11_18
BP4 N/A Not applicable: p.Thr1561 lies outside ENIGMA's BRCA1 functional domains, while BP4's silent-variant path requires an in-domain variant.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18
BP5 Not assessed Not assessed: no variant-specific or combined clinical likelihood ratio was available for comparison with the BP5 thresholds.
cspec vcep_specifications_v1_2_2024_11_18 vcep_pmid_31853058_brca1_clinical_history_lr
BP6 N/A Not applicable: the ENIGMA BRCA1 VCEP explicitly says BP6 is not for use.
cspec vcep_specifications_v1_2_2024_11_18
BP7 Not assessed Not assessed: the outside-domain BP7_Strong (RNA) path requires an mRNA-only assay, but only SpliceAI maximum delta 0.015 is available.
cspec spliceai vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 vcep_pmid_22505045_houdayer_2012_hummutat
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