Variant classification summary

NM_007294.4:c.598G>A

BRCA1 · NP_009225.1:p.(Gly200Arg) · NM_007294.4

GRCh37: chr17:41247935 C>T · GRCh38: chr17:43095918 C>T

Gene: BRCA1 Transcript: NM_007294.4

Final call

VUS

BP1 strong

Variant details

Gene

BRCA1

Transcript

NM_007294.4

Protein

NP_009225.1:p.(Gly200Arg)

gnomAD AF

1.240862598043656e-06 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

VUS: BP1 (strong) applies because Gly200 lies outside the approved BRCA1 domains and SpliceAI is 0.019.

Final determination: Under ENIGMA Table 3, a single Strong benign criterion requires additional qualifying benign evidence from multiple evidence types for Likely Benign, so BP1_Strong alone remains 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.598G>A is a missense variant, whereas ENIGMA PVS1 is restricted to null variants and damaging mRNA consequences.	cspec vcep_specifications_table4_v1_2_2024_11_18 vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 spliceai
PS1	Not assessed	Not assessed: no pathogenic or likely pathogenic comparator producing p.Gly200Arg was identified, although SpliceAI 0.019 meets the VCEP no-splicing condition of <=0.1.	cspec vcep_specifications_v1_2_2024_11_18 spliceai
PS2	N/A	Not applicable: the ENIGMA VCEP prohibits PS2 because BRCA1/2 cancers are common and de novo predictive capacity is uncalibrated.	cspec
PS3	Not assessed	Not assessed: no variant-specific calibrated protein-function assay result was found for c.598G>A/p.Gly200Arg in the governing ENIGMA sources.	cspec vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_humu_40_1557_s001
PS4	Not assessed	Not assessed: no case-control odds ratio, p-value, or confidence interval is available to compare with the ENIGMA PS4 thresholds (OR >=4; p <=0.05; lower CI >2.0).	cspec
PM1	N/A	Not applicable: ENIGMA explicitly excludes PM1, and residue 200 lies outside the listed 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: variant is absent from both specified non-cancer gnomAD datasets, but the required regional average read depth of at least 25 is not reported.	cspec gnomad_v2
PM3	Not assessed	Not assessed: no qualifying Fanconi anemia proband, pathogenic BRCA1 allele in trans, phase information, or Table 6 PM3 points are documented.	cspec
PM4	N/A	Not applicable: p.Gly200Arg changes one amino acid but does not alter protein length, and ENIGMA does not use PM4 for this consequence.	cspec vcep_specifications_v1_2_2024_11_18
PM5	N/A	Not applicable: ENIGMA does not use classic missense PM5, and its PM5_PTC replacement applies only to PVS1-annotated truncating variants.	cspec vcep_specifications_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
PM6	N/A	Not applicable: the ENIGMA VCEP prohibits PM6 because BRCA1/2 cancers are common and de novo predictive capacity is uncalibrated.	cspec
PP1	Not assessed	Not assessed: no affected-family segregation or quantitative LR is available, so the ENIGMA PP1 thresholds cannot be applied.	cspec vcep_humu_40_1557_s001
PP2	N/A	Not applicable: ENIGMA states that missense variants are not a common BRCA1 pathogenic mechanism and therefore excludes PP2.	cspec vcep_specifications_v1_2_2024_11_18
PP3	Not met	Not met: missense REVEL score 0.599 is below the supporting PP3 threshold of >=0.644.	cspec revel
PP4	Not assessed	Not assessed: no combined clinical likelihood ratio is available to compare with the ENIGMA PP4 supporting threshold (LR >=2.08).	cspec vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058 PMID:17924331
PP5	N/A	Not applicable: ENIGMA says do not use PP5, and no exact-variant ClinVar expert-panel pathogenic classification exists.	cspec clinvar
BA1	Not assessed	Not assessed: reported maximum observed AF is 1.6021e-05, below the 0.001 BA1 threshold, but governing FAF and read-depth values are unavailable.	cspec gnomad_v2 gnomad_v4
BS1	Not assessed	Not assessed: highest observed AF is 1.6021e-05, below the 0.00002 BS1 Supporting threshold, but governing FAF and read-depth values are unavailable.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: gnomAD reports 0 homozygotes, but the VCEP excludes frequency data from BS2 and provides no qualifying clinical-cohort observations or age data.	cspec gnomad_v4
BS3	Not assessed	Not assessed: no variant-specific calibrated benign protein-function assay result was found for c.598G>A/p.Gly200Arg in the governing ENIGMA sources.	cspec vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_humu_40_1557_s001
BS4	Not assessed	Not assessed: no affected-family non-segregation or quantitative LR is available, so the ENIGMA BS4 thresholds cannot be applied.	cspec vcep_humu_40_1557_s001
BP1	Met	Met, strong: Gly200 is outside approved BRCA1 domains and SpliceAI max delta 0.019 is below the VCEP <=0.1 no-splicing threshold.	cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 spliceai
BP2	N/A	Not applicable: the ENIGMA BRCA1 specification prohibits BP2 except in the context of BS2, which is not established here.	cspec
BP3	N/A	Not applicable: p.Gly200Arg is a missense substitution, not an in-frame deletion or insertion in a functionless repetitive region.	cspec vcep_specifications_v1_2_2024_11_18
BP4	Not met	Not met: missense REVEL score 0.599 exceeds the supporting BP4 threshold of <=0.29 and is gray-zone.	cspec revel
BP5	Not assessed	Not assessed: no combined clinical likelihood ratio is available to compare with the ENIGMA BP5 supporting threshold (LR <=0.48).	cspec vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058 PMID:17924331
BP6	N/A	Not applicable: ENIGMA says do not use BP6, and no exact-variant ClinVar expert-panel benign classification exists.	cspec clinvar
BP7	N/A	Not applicable: p.Gly200Arg is a missense change, whereas BP7 applies only to synonymous variants.	cspec

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