LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-10-30
Case ID: NM_007294.4_c.181T_G_20261030_121525
Framework: ACMG/AMP 2015 with ENIGMA Table 3 adaptations
Variant classification summary

NM_007294.4:c.181T>G

BRCA1  · NP_009225.1:p.(Cys61Gly)  · NM_007294.4
GRCh37: chr17:41258504 A>C  ·  GRCh38: chr17:43106487 A>C
Gene: BRCA1 Transcript: NM_007294.4
Final call
Pathogenic
PS3 strong PP3 supporting PP4 very strong PP5 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
BRCA1
Transcript
NM_007294.4
Protein
NP_009225.1:p.(Cys61Gly)
gnomAD AF
1.869370857006838e-05 (v4.1)
ClinVar
Pathogenic
OncoKB
Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
Pathogenic: ENIGMA assigns PS3 Strong because calibrated functional testing shows damaging effects for c.181T>G/p.Cys61Gly.
2
Pathogenic: PP3 Supporting is met because BayesDel no-AF is 0.565018, above the BRCA1 threshold of 0.28.
3
Pathogenic: PP4 Very Strong is met because the exact-variant clinical-history LR is 5.517121778727685e+22, above 350:1.
4
Pathogenic: PP5 Supporting is recorded as met in the authoritative criteria from an expert-panel pathogenic classification.
Final determination: Under ENIGMA Table 3, one Very Strong pathogenic criterion plus one Strong pathogenic criterion satisfies Pathogenic; PP4 Very Strong and PS3 Strong meet this rule.
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.181T>G is a missense variant, while ENIGMA PVS1 is limited to null variants and mRNA-only null-variant assays.
cspec vcep_specifications_v1_2_2024_11_18 vcep_specifications_table4_v1_2_2024_11_18 vcep_specifications_table9_v1_2_2024_11_18
PS1 Not assessed Not assessed: c.181T>A p.Cys61Ser is likely pathogenic, but c.181T>G has SpliceAI 0.164 and comparator splicing equivalence is unestablished.
cspec vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001 PMID:31131967 spliceai
PS2 N/A Not applicable: the BRCA1 VCEP explicitly directs that PS2 de novo evidence must not be used.
cspec
PS3 Met Met at Strong: ENIGMA Table 9 pre-assigns PS3 Strong because calibrated functional testing found c.181T>G/p.Cys61Gly similar to pathogenic controls.
cspec vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 PMID:20103620
PS4 Not assessed Not assessed: no independently verified affected-case versus control counts, p-value, odds ratio, or confidence interval are available for c.181T>G.
cspec PMID:20103620
PM1 N/A Not applicable: the VCEP says PM1 is not used, despite residue 61 lying within the defined RING domain at residues 2-101.
cspec vcep_appendices_v1_2_2024_11_18
PM2 Not met Not met: c.181T>G is observed in both required datasets, at 6/236276 non-cancer exome alleles and 4/147958 non-cancer genome alleles.
cspec gnomad_v2 gnomad_v4
PM3 Not met Not met: the only identified co-occurrence had no chromosome fragility, so the VCEP Fanconi Anemia phenotype requirement was not satisfied.
vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18
PM4 N/A Not applicable: p.Cys61Gly is a missense substitution with no protein-length change, and ENIGMA explicitly says PM4 is not used.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
PM5 N/A Not applicable: the VCEP disallows missense PM5, and its repurposed PM5_PTC is restricted to PVS1 protein-termination variants.
cspec vcep_specifications_table4_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18
PM6 N/A Not applicable: the BRCA1 VCEP explicitly directs that PM6 de novo evidence must not be used.
cspec
PP1 Not assessed Not assessed: no quantitative segregation likelihood ratio or family-level genotype and phenotype data are available for this variant.
cspec
PP2 N/A Not applicable: the VCEP says PP2 is not used for BRCA1 because benign missense variants are frequent.
cspec
PP3 Met Met at Supporting: BayesDel no-AF is 0.565018, exceeding the ENIGMA BRCA1 PP3 protein-impact threshold of 0.28 in the RING domain.
cspec vcep_specifications_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 bayesdel spliceai
PP4 Met Met, Very Strong: Li et al. report LR 5.517121778727685e+22, satisfying the ENIGMA PP4 Very Strong threshold of LR >=350:1.
cspec vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058
PP5 Met Not applicable: ENIGMA explicitly instructs that PP5 is not to be used for BRCA1 classifications.
cspec clinvar
BA1 N/A Not applicable: ENIGMA excludes BA1 for this well-established pathogenic founder variant, whose maximum non-cancer filter allele frequency is 2.846e-05, below 0.001.
cspec gnomad_v2 gnomad_v4 vcep_appendices_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18
BS1 N/A Not applicable: ENIGMA excludes BS1 for this well-established pathogenic founder variant, despite a maximum non-cancer filter allele frequency of 2.846e-05.
cspec gnomad_v2 gnomad_v4 vcep_appendices_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18
BS2 Not assessed Not assessed: both non-cancer gnomAD datasets report zero homozygotes, and no qualifying clinical-cohort co-occurrence observation supplies the VCEP BS2 points.
cspec gnomad_v2 gnomad_v4 vcep_appendices_v1_2_2024_11_18
BS3 Not met Not met: ENIGMA Table 9 assigns PS3 Strong, while ST4 classifies c.181T>G/p.Cys61Gly as complete functional impact and LOF.
cspec vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
BS4 Not assessed Not assessed: no quantitative non-segregation likelihood ratio or family-level genotype and phenotype data are available for this variant.
cspec
BP1 Not met Not met: residue 61 is inside the RING domain (aa 2-101) and SpliceAI 0.164 exceeds the required <=0.1 threshold.
cspec vcep_appendices_v1_2_2024_11_18 spliceai
BP2 N/A Not applicable: ENIGMA explicitly says BP2 is not used and is applied only in the context of BS2.
vcep_specifications_v1_2_2024_11_18
BP3 N/A Not applicable: c.181T>G is missense rather than an in-frame insertion/deletion, and ENIGMA explicitly says BP3 is not used.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
BP4 Not met Not met: BayesDel 0.565018 exceeds the BP4 no-impact cutoff of 0.15, and SpliceAI 0.164 exceeds its required maximum of 0.1.
cspec vcep_specifications_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 bayesdel spliceai
BP5 Not met Not met: the clinical-history LR is 5.517121778727685e+22, whereas BP5 Supporting requires LR <=0.48.
cspec vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058
BP6 N/A Not applicable: ENIGMA explicitly instructs that BP6 is not to be used for BRCA1 classifications.
cspec
BP7 N/A Not applicable: BP7_Strong (RNA) covers missense variants outside functional domains, whereas p.Cys61Gly is inside the BRCA1 RING domain at residue 61.
vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
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