Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
This variantScenario
BenignPathogenic
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
About BRCA1
BRCA1 encodes a large nuclear protein that helps maintain genomic stability by coordinating the repair of DNA double-strand breaks through homologous recombination, and it also regulates transcription and the cell cycle. It acts as a tumor suppressor, working with proteins such as RAD51, BRCA2, BARD1, and PALB2 to preserve genome integrity. Inherited alterations in BRCA1 cause hereditary breast and ovarian cancer syndrome, with elevated risks of breast, ovarian, prostate, and pancreatic cancers, and biallelic loss underlies a rare form of Fanconi anemia. Because BRCA1-driven tumors rely on impaired DNA repair, they are treatable with PARP inhibitors.
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Criteria may be applied incorrectly, sources may be misread, and a
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Double-check every criterion and its underlying evidence
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01The reasoning
How it was classified
The recorded framework is ClinGen BRCA1 VCEP v1.2. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. BRCA1, a tumor suppressor involved in the DNA damage response, is mutated in various cancer types.
ACMG/AMP criteria under ClinGen BRCA1 VCEP v1.2, with the data and sources behind each one.
28 criteria with recorded statuses: 1 met · 2 not met · 13 not assessed · 12 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
For the requested consequence/LOF criteria, all three are not applicable: the variant is a missense substitution without a null consequence, protein-length change, or repetitive-region in-frame indel, consistent with ENIGMA BRCA1/2 V1.2.
Among the requested codon, residue, and domain criteria, only BP1_Strong is met under the governing ENIGMA BRCA1 v1.2 specification; PS1 remains not assessed because no qualifying same-amino-acid pathogenic comparator was identified.
PM1, PM5, and PP2 are explicitly not applicable under the ENIGMA framework for this missense variant.
For this missense variant, the applicable computational path is REVEL only. REVEL 0.599 is below the PP3 supporting threshold and above the BP4 supporting threshold, so PP3 and BP4 are not met; BP7 is not_applicable because the variant is not synonymous.
Population assessment follows the ENIGMA BRCA1 VCEP v1.2 rules, which take precedence over generic ACMG thresholds.
The supplied VCEP full-text files contain the governing population rules but no variant-specific pre-assigned entry for c.598G>A, p.Gly200Arg, or p.G200R.
PM2 is not assessed because the variant is absent from both VCEP-specified non-cancer gnomAD datasets but the required regional read depth is not reported; BA1 and BS1 are not assessed because governing FAF and depth values are unavailable; BS2 is not assessed because no qualifying clinical-cohort observations are available.
No criteria match.
Met · 1
BP1StrongMet, strong: Gly200 is outside approved BRCA1 domains and SpliceAI max delta 0.019 is below the VCEP <=0.1 no-splicing threshold.
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Reasoning
The ENIGMA BRCA1 v1.2 specification applies BP1_Strong to missense variants outside a potentially clinically important functional domain when no splicing is predicted (SpliceAI <=0.1). Gly200 is outside the VCEP-defined BRCA1 RING domain aa 2-101, coiled-coil domain aa 1391-1424, and BRCT repeats aa 1650-1857. The case SpliceAI maximum delta is 0.019, which is below the VCEP <=0.1 cutoff. Therefore BP1_Strong is met.
Rule
Apply BP1_Strong for a missense variant outside a potentially clinically important functional domain with SpliceAI <=0.1.
Evidence considered
ENIGMA BRCA1 v1.2 specifies BP1_Strong for silent, missense, or in-frame insertion/deletion variants outside a potentially clinically important functional domain with no predicted splicing (SpliceAI <=0.1).
The VCEP-defined BRCA1 domains are RING aa 2-101, coiled-coil aa 1391-1424, and BRCT repeats aa 1650-1857; residue 200 is outside all three.
SpliceAI reports a maximum delta score of 0.019 for NM_007294.4:c.598G>A, satisfying the VCEP no-predicted-splicing condition.
PP3Not met: missense REVEL score 0.599 is below the supporting PP3 threshold of >=0.644.
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Reasoning
The variant is a missense substitution, so PP3/BP4 must use the missense protein-impact path only. The ENIGMA BRCA1 specification was consulted first, and no variant-level pre-assigned PP3 code was found for c.598G>A, p.Gly200Arg, or p.G200R in SupplementaryTables_V1.2_2024-11-18.xlsx, Specifications_V1.2_2024-11-18.docx, Appendices_V1.2_2024-11-18.docx, or PMID_22505045_Houdayer_2012_HumMutat.pdf. The REVEL score is 0.599, below the supplied ClinGen SVI supporting PP3 threshold of >=0.644 (Pejaver et al. 2022, PMID:36413997), so PP3 is not met. SpliceAI and BayesDel were not used to substitute for the applicable missense REVEL path.
Rule
Missense variant: use the REVEL path only; supporting PP3 requires REVEL >=0.644 when no governing VCEP variant-level pre-assigned code applies.
Evidence considered
The case normalization identifies NM_007294.4:c.598G>A as the missense variant NP_009225.1:p.(Gly200Arg), also p.(G200R).
The ENIGMA BRCA1 v1.2 specification was the governing framework; its PP3 rule was reviewed before applying the supplied generic missense calibration.
The recorded REVEL score is 0.599. The supplied ClinGen SVI calibration defines supporting PP3 at REVEL >=0.644 (Pejaver et al. 2022, PMID:36413997).
Exact searches for c.598G>A, p.Gly200Arg, and p.G200R found no variant-level pre-assigned PP3 entry in the four governing full-text files named in gaps_remaining.
Still missing
No variant-level pre-assigned PP3 entry for c.598G>A, p.Gly200Arg, or p.G200R was found in SupplementaryTables_V1.2_2024-11-18.xlsx.
No variant-level pre-assigned PP3 entry for c.598G>A, p.Gly200Arg, or p.G200R was found in Specifications_V1.2_2024-11-18.docx.
No variant-level pre-assigned PP3 entry for c.598G>A, p.Gly200Arg, or p.G200R was found in Appendices_V1.2_2024-11-18.docx.
No variant-level pre-assigned PP3 entry for c.598G>A, p.Gly200Arg, or p.G200R was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.
BP4Not met: missense REVEL score 0.599 exceeds the supporting BP4 threshold of <=0.29 and is gray-zone.
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Reasoning
The variant is a missense substitution, so PP3/BP4 must use the missense protein-impact path only. The ENIGMA BRCA1 specification was consulted first, and no variant-level pre-assigned BP4 code was found for c.598G>A, p.Gly200Arg, or p.G200R in SupplementaryTables_V1.2_2024-11-18.xlsx, Specifications_V1.2_2024-11-18.docx, Appendices_V1.2_2024-11-18.docx, or PMID_22505045_Houdayer_2012_HumMutat.pdf. The REVEL score is 0.599, above the supplied ClinGen SVI supporting BP4 threshold of <=0.29 and within the gray zone, so BP4 is not met. The SpliceAI score and BayesDel score were not used to substitute for the applicable missense REVEL path.
Rule
Missense variant: use the REVEL path only; supporting BP4 requires REVEL <=0.29 when no governing VCEP variant-level pre-assigned code applies. Gray-zone REVEL does not permit substitution of SpliceAI.
Evidence considered
The case normalization identifies NM_007294.4:c.598G>A as the missense variant NP_009225.1:p.(Gly200Arg), also p.(G200R).
The ENIGMA BRCA1 v1.2 specification was the governing framework; its BP4 rule was reviewed before applying the supplied generic missense calibration.
The recorded REVEL score is 0.599. The supplied ClinGen SVI calibration defines supporting BP4 at REVEL <=0.29 and does not support BP4 in the gray zone above that threshold (Pejaver et al. 2022, PMID:36413997).
Exact searches for c.598G>A, p.Gly200Arg, and p.G200R found no variant-level pre-assigned BP4 entry in the four governing full-text files named in gaps_remaining.
Still missing
No variant-level pre-assigned BP4 entry for c.598G>A, p.Gly200Arg, or p.G200R was found in SupplementaryTables_V1.2_2024-11-18.xlsx.
No variant-level pre-assigned BP4 entry for c.598G>A, p.Gly200Arg, or p.G200R was found in Specifications_V1.2_2024-11-18.docx.
No variant-level pre-assigned BP4 entry for c.598G>A, p.Gly200Arg, or p.G200R was found in Appendices_V1.2_2024-11-18.docx.
No variant-level pre-assigned BP4 entry for c.598G>A, p.Gly200Arg, or p.G200R was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.
PS1Not 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.
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Reasoning
The ENIGMA BRCA1 specification permits PS1 for a missense variant producing the same amino-acid substitution as a previously classified pathogenic variant, provided both variants are considered to act through protein change and have no confirmed or predicted splice effect (SpliceAI <=0.1). This variant is NM_007294.4:c.598G>A, p.(Gly200Arg)/p.(G200R), with SpliceAI maximum delta 0.019, but no pathogenic or likely pathogenic comparator producing p.Gly200Arg was identified in the case evidence or in the required full-text VCEP files. The criterion therefore cannot be assessed from the available comparator evidence rather than being treated as evidence against pathogenicity.
Rule
Apply PS1 for a predicted missense substitution matching a previously classified pathogenic variant at the amino-acid level, when both variants act through protein change and SpliceAI is <=0.1; use PS1_Moderate when the comparator is likely pathogenic.
Evidence considered
ENIGMA BRCA1 v1.2 states that PS1 may be applied when a variant leads to the same missense substitution as a known pathogenic or likely pathogenic variant caused by a different nucleotide change.
The VCEP requires no confirmed or predicted mRNA-splicing effect for the missense PS1 path; the case SpliceAI maximum delta is 0.019, below the <=0.1 condition.
The required VCEP full-text searches found no entry for c.598G>A, p.Gly200Arg, or p.G200R in Specifications_Table4_V1.2_2024-11-18.xlsx.txt, SupplementaryTables_V1.2_2024-11-18.xlsx.txt, Specifications_V1.2_2024-11-18.docx.txt, or Appendices_V1.2_2024-11-18.docx.txt.
Still missing
No p.Gly200Arg, p.G200R, or c.598G>A entry was found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt.
No p.Gly200Arg, p.G200R, or c.598G>A entry was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
No p.Gly200Arg, p.G200R, or c.598G>A entry was found in Specifications_V1.2_2024-11-18.docx.txt.
No p.Gly200Arg, p.G200R, or c.598G>A entry was found in Appendices_V1.2_2024-11-18.docx.txt.
A qualifying previously classified pathogenic or likely pathogenic same-amino-acid comparator is still required for PS1.
PS3Not assessed: no variant-specific calibrated protein-function assay result was found for c.598G>A/p.Gly200Arg in the governing ENIGMA sources.
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Reasoning
The ENIGMA BRCA1/2 specification requires PS3 functional evidence from a well-established in vitro or in vivo assay measuring protein function, or mRNA and protein together, with strength assigned using calibrated results in Table 9. Exact searches for NM_007294.4:c.598G>A, c.598G>A, p.Gly200Arg, and p.G200R found no variant-specific entry in Specifications_Table9_V1.2_2024-11-18.xlsx.txt, SupplementaryTables_V1.2_2024-11-18.xlsx.txt, Appendices_V1.2_2024-11-18.docx.txt, or HUMU-40-1557-s001.xlsx.txt. The case materials provide no variant-specific functional assay result or extracted publication finding, so PS3 cannot be assigned.
Rule
ENIGMA BRCA1/2 V1.2: apply PS3 for well-established in vitro or in vivo functional studies supportive of a damaging effect when the assay measures protein function only or mRNA and protein combined; use calibrated variant-specific recommendations in Table 9.
Evidence considered
ENIGMA Table 1 specifies PS3 for well-established functional studies supportive of a damaging effect when the assay measures protein function alone or mRNA and protein together; calibrated variant-specific recommendations are provided in Table 9.
Exact searches of the declared functional VCEP full-text files for c.598G>A, p.Gly200Arg, and p.G200R returned no matching variant entry.
The case evidence bundle has an empty paper_extracts object and reports no literature PMIDs for this case; no variant-specific assay result is therefore available to support PS3.
Still missing
No c.598G>A, p.Gly200Arg, or p.G200R entry in Specifications_Table9_V1.2_2024-11-18.xlsx.txt.
No c.598G>A, p.Gly200Arg, or p.G200R entry in SupplementaryTables_V1.2_2024-11-18.xlsx.txt, including ST4 functional assay results.
No c.598G>A, p.Gly200Arg, or p.G200R entry in Appendices_V1.2_2024-11-18.docx.txt.
No c.598G>A, p.Gly200Arg, or p.G200R entry in HUMU-40-1557-s001.xlsx.txt.
No variant-specific functional publication extraction was available in paper_extracts.json, and the case literature packet contained no PMIDs.
PS4Not 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).
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Reasoning
The governing ENIGMA BRCA1 specification requires case-control evidence with p-value <=0.05, OR >=4, and a lower confidence interval excluding 2.0. The case materials provide no case-control counts, odds ratio, p-value, or confidence interval for NM_007294.4:c.598G>A (p.Gly200Arg/p.G200R), so PS4 cannot be assessed. The variant was explicitly searched under all three notations in Specifications_V1.2_2024-11-18.docx.txt, PMID_31853058_BRCA1_clinical_history_LR.xlsx.txt, PMID_31853058_Li_2020_GeneticsInMedicine.pdf.txt, and PMID_17924331_Easton_2007_AJHG.pdf.txt; no exact-variant entry was found in those files.
Rule
Case-control studies; p-value <=0.05 and OR >=4 (lower confidence interval excludes 2.0).
Evidence considered
ENIGMA BRCA1 Specification v1.2 states: "Case-control studies; p-value <=0.05 and OR >=4 (lower confidence interval excludes 2.0)."
The case evidence contains no variant-specific case-control effect estimate or significance statistics for NM_007294.4:c.598G>A (p.Gly200Arg/p.G200R).
Still missing
No case-control counts, odds ratio, p-value, or confidence interval for NM_007294.4:c.598G>A.
No exact-variant entry found after searching c.598G>A, p.Gly200Arg, and p.G200R in Specifications_V1.2_2024-11-18.docx.txt.
No exact-variant entry found after searching c.598G>A, p.Gly200Arg, and p.G200R in PMID_31853058_BRCA1_clinical_history_LR.xlsx.txt.
No exact-variant entry found after searching c.598G>A, p.Gly200Arg, and p.G200R in PMID_31853058_Li_2020_GeneticsInMedicine.pdf.txt.
No exact-variant entry found after searching c.598G>A, p.Gly200Arg, and p.G200R in PMID_17924331_Easton_2007_AJHG.pdf.txt.
PM2Not 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.
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Reasoning
The ENIGMA BRCA1 VCEP specifies PM2 Supporting for absence from controls in gnomAD v2.1 non-cancer exomes and gnomAD v3.1 non-cancer genomes, provided regional average read depth is at least 25. The case evidence reports the variant absent from both specified non-cancer datasets, and no indel exception applies because this is a missense SNV. However, the required regional read-depth value is not reported, so the full governing PM2 rule cannot be confirmed.
Rule
ENIGMA PM2 Supporting: absent from gnomAD v2.1 non-cancer exome-only and gnomAD v3.1 non-cancer controls; regional average read depth must be at least 25.
Evidence considered
ENIGMA BRCA1 VCEP PM2 Supporting rule: absent from controls in gnomAD v2.1 non-cancer exome-only data and gnomAD v3.1 non-cancer genome data, with regional average read depth at least 25.
The case bundle reports the variant absent from gnomAD v2.1 non-cancer and absent from gnomAD v3.1 non-cancer.
The variant is a missense single-nucleotide substitution, so the VCEP exclusion for insertion, deletion, or delins variants does not apply.
The four supplied on-record VCEP full-text files were searched for c.598G>A, p.Gly200Arg, and p.G200R; no variant-specific PM2 pre-assigned entry was found.
Still missing
No variant-specific entry for c.598G>A, p.Gly200Arg, or p.G200R was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
No variant-specific entry for c.598G>A, p.Gly200Arg, or p.G200R was found in Specifications_V1.2_2024-11-18.docx.txt.
No variant-specific entry for c.598G>A, p.Gly200Arg, or p.G200R was found in Appendices_V1.2_2024-11-18.docx.txt.
No variant-specific entry for c.598G>A, p.Gly200Arg, or p.G200R was found in HUMU-40-1557-s001.xlsx.txt.
Regional average read depth at the variant is not reported and should be confirmed against the VCEP minimum of 25.
PM3Not assessed: no qualifying Fanconi anemia proband, pathogenic BRCA1 allele in trans, phase information, or Table 6 PM3 points are documented.
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Reasoning
The ENIGMA BRCA1 VCEP specification limits PM3 to patients with a phenotype consistent with BRCA1-related Fanconi anemia and a co-occurring pathogenic or likely pathogenic BRCA1 variant, with PM3 strength assigned from Table 6 points for phase and phenotype. The available case evidence contains no affected-proband observation, Fanconi anemia phenotype, pathogenic variant in trans or cis, phase information, or qualifying homozygous observation for NM_007294.4:c.598G>A (p.Gly200Arg/p.G200R). Therefore PM3 cannot be assigned.
Rule
ENIGMA BRCA1 PM3_VariableWeight: apply only for a patient with phenotype consistent with BRCA1-related Fanconi anemia and co-occurring pathogenic or likely pathogenic variants in the same gene; assign strength from Table 6 PM3 points.
Evidence considered
The governing ENIGMA BRCA1 specification states that PM3 applies for a patient with a phenotype consistent with BRCA1- or BRCA2-related Fanconi anemia and co-occurring variants in the same gene.
ENIGMA Table 6 assigns 2 points for a pathogenic or likely pathogenic variant in trans or homozygous with a qualifying Fanconi anemia phenotype, 1 point when phase is unknown, and requires 4 or more total points for PM3_Strong, 2 points for PM3, or 1 point for PM3_Supporting.
The reviewed case evidence provides no qualifying Fanconi anemia phenotype, affected-proband allelic observation, pathogenic BRCA1 variant in trans, or documented phase for this variant.
Still missing
No entry for c.598G>A, p.Gly200Arg, or p.G200R was found in Specifications_V1.2_2024-11-18.docx.txt, the governing ENIGMA specification searched for this criterion.
Case-level phase, affected-proband phenotype, co-occurring pathogenic or likely pathogenic BRCA1 variant, and qualifying Fanconi anemia observations are not documented.
PP1Not assessed: no affected-family segregation or quantitative LR is available, so the ENIGMA PP1 thresholds cannot be applied.
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Reasoning
The ENIGMA VCEP permits PP1 only when quantitative co-segregation evidence is available and assigns strength by likelihood ratio: supporting at LR ≥2.08, moderate at LR ≥4.3, strong at LR ≥18.7, and very strong at LR ≥350. The case evidence contains no affected-family segregation data, meioses, or quantitative co-segregation LR for NM_007294.4:c.598G>A (p.Gly200Arg/p.G200R). The governing HUMU-40-1557-s001 file was searched under c.598G>A, p.Gly200Arg, and p.G200R and contains no entry for this variant.
Rule
PP1_VariableWeight: assign by quantitative co-segregation LR; supporting ≥2.08:1, moderate ≥4.3:1, strong ≥18.7:1, very strong ≥350:1.
Evidence considered
ENIGMA BRCA1/2 Specification v1.2 Table 1: PP1 is based on quantitative co-segregation analysis, with LR thresholds of ≥2.08 supporting, ≥4.3 moderate, ≥18.7 strong, and ≥350 very strong.
The consolidated case-evidence bundle contains no proband, parent, affected-relative, meiosis, pedigree, or quantitative co-segregation result for this variant.
HUMU-40-1557-s001.xlsx.txt was searched for c.598G>A, p.Gly200Arg, and p.G200R; no variant-specific entry was found.
Still missing
No proband-level pedigree, affected-relative testing, informative meioses, or quantitative co-segregation LR is present in the case evidence.
No entry for c.598G>A, p.Gly200Arg, or p.G200R was found in HUMU-40-1557-s001.xlsx.txt, the governing multifactorial VCEP file searched.
PP4Not assessed: no combined clinical likelihood ratio is available to compare with the ENIGMA PP4 supporting threshold (LR >=2.08).
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Reasoning
The governing ENIGMA specification restricts PP4 to clinically calibrated multifactorial likelihood evidence and requires a combined LR >=2.08 for supporting evidence, with higher strengths at >=4.3, >=18.7, and >=350. The case materials provide no clinical-history, co-segregation, co-occurrence, pathology, or combined likelihood ratio for this variant. The BRCA1 clinical-history table was searched for c.598G>A and returned no exact-variant row; the Li and Easton papers provide methodology but no exact-variant evidence in the searched text.
Rule
PP4 supporting requires combined LR >=2.08; moderate >=4.3; strong >=18.7; very strong >=350.
Evidence considered
ENIGMA BRCA1 Specification v1.2 states that PP4 is used only for combined clinically calibrated likelihood evidence and requires PP4 supporting at LR >=2.08, moderate at LR >=4.3, strong at LR >=18.7, and very strong at LR >=350.
The BRCA1 clinical-history table contains no exact c.598G>A/p.Gly200Arg/p.G200R row, and the case materials contain no other combined clinical LR for this variant.
Li et al. 2020 describes a personal/family-history logistic-regression LR methodology, while Easton et al. 2007 describes combining co-occurrence, clinical-history, and cosegregation LRs; neither searched full text mentions this exact variant.
Still missing
No combined clinical LR or component LR data for this variant.
No exact-variant entry found in PMID_31853058_BRCA1_clinical_history_LR.xlsx.txt.
No exact-variant entry found in PMID_31853058_Li_2020_GeneticsInMedicine.pdf.txt.
No exact-variant entry found in PMID_17924331_Easton_2007_AJHG.pdf.txt.
BA1Not assessed: reported maximum observed AF is 1.6021e-05, below the 0.001 BA1 threshold, but governing FAF and read-depth values are unavailable.
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Reasoning
The ENIGMA BRCA1 VCEP requires BA1 when the maximum filter allele frequency (FAF) exceeds 0.001 (0.1%) in gnomAD v2.1 non-cancer exomes and/or gnomAD v3.1 non-cancer genomes, with read depth at least 20. The case data report gnomAD v2.1 non-cancer absence and gnomAD v3.1 non-cancer absence, and gnomAD v4.1 total AF 1.2408626e-06 with highest observed subpopulation AF 1.6021020e-05, but no FAF or regional read-depth value is reported. Therefore the governing FAF-based BA1 rule cannot be fully assessed, although the reported allele frequencies are far below 0.001.
Rule
ENIGMA BA1: FAF > 0.001 in gnomAD v2.1 non-cancer exome-only and/or gnomAD v3.1 non-cancer non-founder data; do not apply if read depth <20.
Evidence considered
ENIGMA BRCA1 VCEP BA1 rule: apply only when FAF is above 0.001 in gnomAD v2.1 non-cancer exomes and/or gnomAD v3.1 non-cancer genomes, with read depth at least 20.
The case bundle reports absence from gnomAD v2.1 non-cancer and gnomAD v3.1 non-cancer.
The case bundle reports gnomAD v4.1 total AF 1.2408626e-06 (2/1,611,782 alleles), highest observed subpopulation AF 1.6021020e-05 (1/62,418 alleles), and zero homozygotes; FAF fields are null.
The four supplied on-record VCEP full-text files were searched for c.598G>A, p.Gly200Arg, and p.G200R; no variant-specific BA1 entry was found.
Still missing
No variant-specific entry for c.598G>A, p.Gly200Arg, or p.G200R was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
No variant-specific entry for c.598G>A, p.Gly200Arg, or p.G200R was found in Specifications_V1.2_2024-11-18.docx.txt.
No variant-specific entry for c.598G>A, p.Gly200Arg, or p.G200R was found in Appendices_V1.2_2024-11-18.docx.txt.
No variant-specific entry for c.598G>A, p.Gly200Arg, or p.G200R was found in HUMU-40-1557-s001.xlsx.txt.
gnomAD filter allele frequency and regional average read depth are not reported in the case evidence.
BS1Not assessed: highest observed AF is 1.6021e-05, below the 0.00002 BS1 Supporting threshold, but governing FAF and read-depth values are unavailable.
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Reasoning
The ENIGMA BRCA1 VCEP requires BS1 Strong when FAF exceeds 0.0001, or BS1 Supporting when FAF is greater than 0.00002 and no more than 0.0001, in gnomAD v2.1 non-cancer exomes and/or gnomAD v3.1 non-cancer genomes, with read depth at least 20. The case data report absence from both specified non-cancer datasets and gnomAD v4.1 highest observed AF of 1.6021020e-05, below 0.00002, but the governing FAF and read-depth values are not reported. Thus the formal FAF-based rule cannot be fully assessed.
Rule
ENIGMA BS1: FAF >0.0001 for Strong or >0.00002 to <=0.0001 for Supporting in gnomAD v2.1 non-cancer exome-only and/or gnomAD v3.1 non-cancer non-founder data; do not apply if read depth <20.
Evidence considered
ENIGMA BRCA1 VCEP BS1 rule: FAF >0.0001 gives BS1 Strong; FAF >0.00002 and <=0.0001 gives BS1 Supporting; use gnomAD v2.1 non-cancer exomes and/or gnomAD v3.1 non-cancer genomes and require read depth at least 20.
The case bundle reports absence from gnomAD v2.1 non-cancer and gnomAD v3.1 non-cancer.
The case bundle reports gnomAD v4.1 highest observed AF 1.6021020e-05 (1/62,418 alleles), total AF 1.2408626e-06, and zero homozygotes; FAF fields are null.
The four supplied on-record VCEP full-text files were searched for c.598G>A, p.Gly200Arg, and p.G200R; no variant-specific BS1 entry was found.
Still missing
No variant-specific entry for c.598G>A, p.Gly200Arg, or p.G200R was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
No variant-specific entry for c.598G>A, p.Gly200Arg, or p.G200R was found in Specifications_V1.2_2024-11-18.docx.txt.
No variant-specific entry for c.598G>A, p.Gly200Arg, or p.G200R was found in Appendices_V1.2_2024-11-18.docx.txt.
No variant-specific entry for c.598G>A, p.Gly200Arg, or p.G200R was found in HUMU-40-1557-s001.xlsx.txt.
gnomAD filter allele frequency and regional average read depth are not reported in the case evidence.
BS2Not assessed: gnomAD reports 0 homozygotes, but the VCEP excludes frequency data from BS2 and provides no qualifying clinical-cohort observations or age data.
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Reasoning
The ENIGMA BRCA1 VCEP BS2 rule requires phenotyped clinical or research-cohort observations in healthy adults or individuals meeting specified age/cancer criteria, absence of Fanconi Anemia features, and point accumulation from qualifying heterozygous, homozygous, or phase-unknown observations. The case evidence reports zero homozygotes in gnomAD v4.1 and no homozygote observations in the specified non-cancer gnomAD datasets, but frequency-database observations cannot be used for the VCEP BS2 points system and no qualifying clinical-cohort observations, ages, follow-up, phase, or Fanconi Anemia assessment are provided.
Rule
ENIGMA BS2: apply only from qualifying clinical/research-cohort observations without Fanconi Anemia features; BS2 requires >=4 points, BS2 Moderate 2 points, and BS2 Supporting 1 point; do not use gnomAD frequency observations for these points.
Evidence considered
ENIGMA BRCA1 VCEP BS2 requires qualifying clinical or research-cohort observations and assigns BS2, BS2 Moderate, or BS2 Supporting from >=4, 2, or 1 points, respectively; gnomAD frequency observations are explicitly excluded from this points system.
The case bundle reports zero gnomAD v4.1 homozygotes and no homozygotes in the reported population groups.
No qualifying healthy-adult or age-stratified clinical observations, phase data, follow-up, or Fanconi Anemia phenotype assessment are present.
The four supplied on-record VCEP full-text files were searched for c.598G>A, p.Gly200Arg, and p.G200R; no variant-specific BS2 entry was found.
Still missing
No variant-specific entry for c.598G>A, p.Gly200Arg, or p.G200R was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
No variant-specific entry for c.598G>A, p.Gly200Arg, or p.G200R was found in Specifications_V1.2_2024-11-18.docx.txt.
No variant-specific entry for c.598G>A, p.Gly200Arg, or p.G200R was found in Appendices_V1.2_2024-11-18.docx.txt.
No variant-specific entry for c.598G>A, p.Gly200Arg, or p.G200R was found in HUMU-40-1557-s001.xlsx.txt.
No qualifying clinical or research-cohort BS2 observations, ages/follow-up, phase, or Fanconi Anemia phenotype data are available.
BS3Not assessed: no variant-specific calibrated benign protein-function assay result was found for c.598G>A/p.Gly200Arg in the governing ENIGMA sources.
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Reasoning
The ENIGMA BRCA1/2 specification requires BS3 benign functional evidence from a well-established in vitro or in vivo assay showing no damaging effect on protein function, measured by protein alone or mRNA and protein together; mRNA-only evidence is handled under an alternative RNA code. Exact searches for NM_007294.4:c.598G>A, c.598G>A, p.Gly200Arg, and p.G200R found no variant-specific entry in Specifications_Table9_V1.2_2024-11-18.xlsx.txt, SupplementaryTables_V1.2_2024-11-18.xlsx.txt, Appendices_V1.2_2024-11-18.docx.txt, or HUMU-40-1557-s001.xlsx.txt. The case materials provide no variant-specific benign functional assay result or extracted publication finding, so BS3 cannot be assigned.
Rule
ENIGMA BRCA1/2 V1.2: apply BS3 for well-established in vitro or in vivo functional studies showing no damaging effect on protein function when the assay measures protein function only or mRNA and protein combined; mRNA-only evidence is assigned under the alternative RNA code.
Evidence considered
ENIGMA Table 1 specifies BS3 for well-established functional studies showing no damaging effect on protein function when the assay measures protein function alone or mRNA and protein together; calibrated variant-specific recommendations are provided in Table 9.
Exact searches of the declared functional VCEP full-text files for c.598G>A, p.Gly200Arg, and p.G200R returned no matching variant entry.
The case evidence bundle has an empty paper_extracts object and reports no literature PMIDs for this case; no variant-specific assay result is therefore available to support BS3.
Still missing
No c.598G>A, p.Gly200Arg, or p.G200R entry in Specifications_Table9_V1.2_2024-11-18.xlsx.txt.
No c.598G>A, p.Gly200Arg, or p.G200R entry in SupplementaryTables_V1.2_2024-11-18.xlsx.txt, including ST4 functional assay results.
No c.598G>A, p.Gly200Arg, or p.G200R entry in Appendices_V1.2_2024-11-18.docx.txt.
No c.598G>A, p.Gly200Arg, or p.G200R entry in HUMU-40-1557-s001.xlsx.txt.
No variant-specific functional publication extraction was available in paper_extracts.json, and the case literature packet contained no PMIDs.
BS4Not assessed: no affected-family non-segregation or quantitative LR is available, so the ENIGMA BS4 thresholds cannot be applied.
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Reasoning
The ENIGMA VCEP permits BS4 only when quantitative non-segregation evidence is available and assigns strength by likelihood ratio: supporting at LR ≤0.48, moderate at LR ≤0.23, strong at LR ≤0.05, and very strong at LR ≤0.00285. The case evidence contains no affected-family non-segregation data, tested affected relatives, meioses, or quantitative LR for NM_007294.4:c.598G>A (p.Gly200Arg/p.G200R). The governing HUMU-40-1557-s001 file was searched under c.598G>A, p.Gly200Arg, and p.G200R and contains no entry for this variant.
Rule
BS4_VariableWeight: assign by quantitative non-segregation LR; supporting ≤0.48:1, moderate ≤0.23:1, strong ≤0.05:1, very strong ≤0.00285:1.
Evidence considered
ENIGMA BRCA1/2 Specification v1.2 Table 1: BS4 is based on quantitative lack of segregation, with LR thresholds of ≤0.48 supporting, ≤0.23 moderate, ≤0.05 strong, and ≤0.00285 very strong.
The consolidated case-evidence bundle contains no affected-relative testing, non-segregation observation, meiosis, pedigree, or quantitative BS4 LR for this variant.
HUMU-40-1557-s001.xlsx.txt was searched for c.598G>A, p.Gly200Arg, and p.G200R; no variant-specific entry was found.
Still missing
No tested affected relatives, non-segregating family observations, informative meioses, or quantitative non-segregation LR is present in the case evidence.
No entry for c.598G>A, p.Gly200Arg, or p.G200R was found in HUMU-40-1557-s001.xlsx.txt, the governing multifactorial VCEP file searched.
BP5Not assessed: no combined clinical likelihood ratio is available to compare with the ENIGMA BP5 supporting threshold (LR <=0.48).
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Reasoning
The governing ENIGMA specification restricts BP5 to clinically calibrated multifactorial likelihood evidence against pathogenicity, with supporting evidence requiring LR <=0.48, moderate <=0.23, strong <=0.05, and very strong <=0.00285. No combined clinical LR or alternate molecular basis is documented for this variant. The BRCA1 clinical-history table and the Li and Easton source texts were searched under c.598G>A, p.Gly200Arg, and p.G200R; no exact-variant entry was found.
Rule
BP5 supporting requires LR <=0.48; moderate <=0.23; strong <=0.05; very strong <=0.00285.
Evidence considered
ENIGMA BRCA1 Specification v1.2 states that BP5 is used only for combined likelihood evidence against pathogenicity: supporting LR <=0.48, moderate LR <=0.23, strong LR <=0.05, and very strong LR <=0.00285.
The BRCA1 clinical-history table contains no exact c.598G>A/p.Gly200Arg/p.G200R row, and the case materials contain no combined LR or documented alternate molecular basis.
Li et al. 2020 and Easton et al. 2007 were reviewed for methodology; neither searched full text mentions this exact variant.
Still missing
No combined clinical LR or documented alternate molecular basis for this variant.
No exact-variant entry found in PMID_31853058_BRCA1_clinical_history_LR.xlsx.txt.
No exact-variant entry found in PMID_31853058_Li_2020_GeneticsInMedicine.pdf.txt.
No exact-variant entry found in PMID_17924331_Easton_2007_AJHG.pdf.txt.
Not applicable · 12· recorded as not applicableShow reasons ▾Hide reasons ▴PVS1N/ANot applicable: c.598G>A is a missense variant, whereas ENIGMA PVS1 is restricted to null variants and damaging mRNA consequences.
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Reasoning
NM_007294.4:c.598G>A is a missense substitution, NP_009225.1:p.(Gly200Arg), located in BRCA1 exon 9 (legacy exon 10), not a nonsense, frameshift, canonical splice-site, initiation-codon, or exon-deletion variant. The ENIGMA BRCA1 V1.2 specification restricts PVS1 to null variants and mRNA assays demonstrating a damaging transcript consequence; no applicable PVS1 decision-table entry was found for c.598G>A, p.Gly200Arg, or p.G200R. SpliceAI max delta is 0.02, providing no evidence that this missense variant should be treated as a splice-null allele.
Rule
ENIGMA BRCA1/2 V1.2 PVS1 null-variant rule; PVS1 is not applicable to this missense substitution.
Evidence considered
The case normalization identifies NM_007294.4:c.598G>A as NP_009225.1:p.(Gly200Arg), also p.(G200R), a missense substitution; c.598 lies within the BRCA1 exon-9 coding interval c.594-c.670.
ENIGMA BRCA1/2 V1.2 defines PVS1 for null variants including nonsense, frameshift, canonical +/-1,2 splice-site, initiation-codon, and exon-deletion variants, with mRNA-only damaging assays handled as PVS1 (RNA).
SpliceAI reports DS_AG 0.019, DS_AL 0.000, DS_DG 0.011, and DS_DL 0.000; the maximum delta is 0.02, so the available splice prediction does not support a splice-null consequence.
Still missing
No exact c.598G>A, p.Gly200Arg, or p.G200R entry found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt.
No exact c.598G>A, p.Gly200Arg, or p.G200R entry found in Specifications_V1.2_2024-11-18.docx.txt.
No exact c.598G>A, p.Gly200Arg, or p.G200R entry found in Appendices_V1.2_2024-11-18.docx.txt.
No exact c.598G>A, p.Gly200Arg, or p.G200R entry found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
PS2VCEPNot applicable: the ENIGMA VCEP prohibits PS2 because BRCA1/2 cancers are common and de novo predictive capacity is uncalibrated.
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Reasoning
The ENIGMA BRCA1/2 VCEP specification explicitly states that PS2 is not to be used because BRCA1/2-related cancers occur relatively commonly and the predictive capacity of de novo occurrences has not been calibrated.
VCEP rule
PS2: Do not use.
Evidence considered
ENIGMA BRCA1/2 Specification v1.2 Table 1: PS2 — Do not use; BRCA1/2-related cancers occur relatively commonly and no calibration exists for de novo occurrences.
PM1VCEPNot applicable: ENIGMA explicitly excludes PM1, and residue 200 lies outside the listed RING, coiled-coil, and BRCT domains.
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Reasoning
The ENIGMA BRCA1 v1.2 specification explicitly designates PM1 as not applicable and directs domain-related missense evidence to BP1, BP4, and PP3 instead. The case variant is p.Gly200Arg, outside the VCEP-defined BRCA1 RING domain (aa 2-101), coiled-coil domain (aa 1391-1424), and BRCT repeats (aa 1650-1857); vcep_materials.json has no domain_tables entry that supersedes these VCEP rules.
VCEP rule
PM1 is not applicable under the ENIGMA BRCA1/2 specification; use the VCEP bioinformatic domain framework instead.
Evidence considered
ENIGMA BRCA1 v1.2 Table 1 states PM1 is not applicable and that the relevant missense domain evidence is evaluated under BP1, BP4, and PP3.
The VCEP-defined BRCA1 clinically important domains are RING aa 2-101, coiled-coil aa 1391-1424, and BRCT repeats aa 1650-1857.
The case residue is Gly200, and vcep_materials.json reports no gene-specific domain_tables entry.
PM4VCEPNot applicable: p.Gly200Arg changes one amino acid but does not alter protein length, and ENIGMA does not use PM4 for this consequence.
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Reasoning
The variant is a single amino-acid substitution, p.Gly200Arg, with no protein length change, in-frame insertion/deletion, delins, or stop-loss consequence. ENIGMA BRCA1/2 V1.2 explicitly states that PM4 is not used and is captured, where relevant, through the bioinformatic analysis framework; that framework does not convert this missense substitution into PM4.
VCEP rule
ENIGMA BRCA1/2 V1.2 PM4 rule: do not use; PM4 concerns protein-length changes, not single-residue substitutions.
Evidence considered
The normalized consequence is missense, NP_009225.1:p.(Gly200Arg), so the encoded protein length remains unchanged.
ENIGMA BRCA1/2 V1.2 describes PM4 as protein length changes from in-frame deletions/insertions in non-repeat regions or stop-loss variants and specifies that PM4 is not used.
Still missing
No exact c.598G>A, p.Gly200Arg, or p.G200R entry found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt.
No exact c.598G>A, p.Gly200Arg, or p.G200R entry found in Specifications_V1.2_2024-11-18.docx.txt.
No exact c.598G>A, p.Gly200Arg, or p.G200R entry found in Appendices_V1.2_2024-11-18.docx.txt.
No exact c.598G>A, p.Gly200Arg, or p.G200R entry found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
PM5N/ANot applicable: ENIGMA does not use classic missense PM5, and its PM5_PTC replacement applies only to PVS1-annotated truncating variants.
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Reasoning
The ENIGMA BRCA1 v1.2 specification explicitly states that classic missense PM5 is not used and is considered within the bioinformatic analysis (PP3/BP4). Its repurposed PM5 code is PM5_VariableWeight (PTC), which applies only to protein-termination-codon variants in an exon and provides additional weight for variants already annotated with PVS1. This variant is a missense substitution, not a PTC or truncating variant, so PM5 is not applicable.
Rule
Do not apply classic missense PM5; apply PM5_VariableWeight (PTC) only for qualifying genomic PTC variants annotated with PVS1, using exon-specific VCEP weights.
Evidence considered
ENIGMA BRCA1 v1.2 states that classic missense PM5 is not used and is considered as part of the PP3/BP4 bioinformatic analysis.
The repurposed PM5_VariableWeight (PTC) code is restricted to genomic protein-termination-codon variants and is used to add weight to variants annotated as PVS1.
The case consequence is missense, p.(Gly200Arg), so the PM5_PTC rule does not apply.
PM6VCEPNot applicable: the ENIGMA VCEP prohibits PM6 because BRCA1/2 cancers are common and de novo predictive capacity is uncalibrated.
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Reasoning
The ENIGMA BRCA1/2 VCEP specification explicitly states that PM6 is not to be used because BRCA1/2-related cancers occur relatively commonly and the predictive capacity of de novo occurrences has not been calibrated.
VCEP rule
PM6: Do not use.
Evidence considered
ENIGMA BRCA1/2 Specification v1.2 Table 1: PM6 — Do not use; BRCA1/2-related cancers occur relatively commonly and no calibration exists for de novo occurrences.
PP2VCEPNot applicable: ENIGMA states that missense variants are not a common BRCA1 pathogenic mechanism and therefore excludes PP2.
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Reasoning
The ENIGMA BRCA1 v1.2 specification explicitly marks PP2 as not applicable because missense variants are not a common mechanism of pathogenicity for BRCA1 and BRCA2 and benign missense variation is sufficiently frequent for the generic PP2 premise not to hold.
VCEP rule
PP2 is not applicable under the ENIGMA BRCA1/2 specification.
Evidence considered
ENIGMA BRCA1 v1.2 Table 1 marks PP2 as not applicable and explains that missense variants are not a common mechanism of pathogenicity for BRCA1/2.
PP5VCEPNot applicable: ENIGMA says do not use PP5, and no exact-variant ClinVar expert-panel pathogenic classification exists.
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Reasoning
The governing ENIGMA BRCA1 specification explicitly states that PP5 is not for use. Independently, the case has no exact-variant ClinVar expert-panel pathogenic or likely pathogenic classification: ClinVar matching was not exact, the selected record was c.934G>A (p.Gly312Ser), and the only submission was a non-expert single-laboratory uncertain-significance assertion.
VCEP rule
Do not use PP5 under the governing ENIGMA BRCA1 specification; an exact-variant expert-panel pathogenic/likely pathogenic classification would also be required by the criterion instructions.
Evidence considered
ENIGMA BRCA1 Specification v1.2 lists PP5 as "Do not use."
ClinVar did not validate an exact match; the candidate record was NM_007294.4(BRCA1):c.934G>A (p.Gly312Ser), and its single GeneDx submission was non-expert, single-submitter, and uncertain significance.
BP2VCEPNot applicable: the ENIGMA BRCA1 specification prohibits BP2 except in the context of BS2, which is not established here.
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Reasoning
The ENIGMA BRCA1 VCEP specification explicitly states that BP2 is not used and is applied only in the context of BS2. BRCA1-related cancer predisposition is treated as an autosomal dominant disorder in the governing framework, and the case evidence does not establish a BS2 observation that would activate this restricted rule. BP2 is therefore not applicable.
VCEP rule
ENIGMA BRCA1 BP2: do not use; apply only in the context of BS2.
Evidence considered
The governing ENIGMA BRCA1 specification states for BP2: observed in trans with a pathogenic variant for a fully penetrant dominant disorder, or observed in cis with a pathogenic variant in any inheritance pattern; do not use, applied only in the context of BS2.
The governing framework identifies BRCA1-related cancer predisposition as autosomal dominant, but the case evidence does not establish the BS2 context required by the VCEP for BP2.
Still missing
No entry for c.598G>A, p.Gly200Arg, or p.G200R was found in Specifications_V1.2_2024-11-18.docx.txt, the governing ENIGMA specification searched for this criterion.
BP3VCEPNot applicable: p.Gly200Arg is a missense substitution, not an in-frame deletion or insertion in a functionless repetitive region.
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Reasoning
BP3 applies to in-frame deletions or insertions in a repetitive region without a known function. NM_007294.4:c.598G>A is a missense substitution producing p.Gly200Arg, not an in-frame deletion or insertion, and no repeat-region protein-length event is present. ENIGMA BRCA1/2 V1.2 explicitly marks BP3 as not used and directs relevant computational/domain assessment to BP4 instead.
VCEP rule
ENIGMA BRCA1/2 V1.2 BP3 rule: do not use; BP3 is limited to repetitive-region in-frame insertions/deletions.
Evidence considered
The variant consequence is missense, NP_009225.1:p.(Gly200Arg), rather than an in-frame insertion or deletion.
ENIGMA BRCA1/2 V1.2 defines BP3 for in-frame deletions/insertions in repetitive regions without known function and explicitly specifies BP3 as not used.
Still missing
No exact c.598G>A, p.Gly200Arg, or p.G200R entry found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt.
No exact c.598G>A, p.Gly200Arg, or p.G200R entry found in Specifications_V1.2_2024-11-18.docx.txt.
No exact c.598G>A, p.Gly200Arg, or p.G200R entry found in Appendices_V1.2_2024-11-18.docx.txt.
No exact c.598G>A, p.Gly200Arg, or p.G200R entry found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
BP6VCEPNot applicable: ENIGMA says do not use BP6, and no exact-variant ClinVar expert-panel benign classification exists.
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Reasoning
The governing ENIGMA BRCA1 specification explicitly states that BP6 is not for use. In addition, ClinVar provides no exact-variant expert-panel benign or likely benign classification: the match was not exact and the only submission was a non-expert single-laboratory uncertain-significance assertion.
VCEP rule
Do not use BP6 under the governing ENIGMA BRCA1 specification; an exact-variant expert-panel benign/likely benign classification would also be required by the criterion instructions.
Evidence considered
ENIGMA BRCA1 Specification v1.2 lists BP6 as "Do not use."
ClinVar did not validate an exact match; the candidate record was c.934G>A (p.Gly312Ser), and its single GeneDx submission was non-expert, single-submitter, and uncertain significance.
BP7N/ANot applicable: p.Gly200Arg is a missense change, whereas BP7 applies only to synonymous variants.
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Reasoning
BP7 applies only to synonymous variants. This variant is missense, NM_007294.4:c.598G>A, p.(Gly200Arg), so BP7 is out of scope and no predictor evaluation is applicable.
Rule
BP7 applies only to synonymous variants; this missense variant is not_applicable.
Evidence considered
The case normalization identifies NM_007294.4:c.598G>A as the missense variant NP_009225.1:p.(Gly200Arg), also p.(G200R).
The ENIGMA BRCA1 v1.2 framework limits BP7 to synonymous or specified noncoding contexts; a missense variant is outside BP7 scope.
0 alternate alleles recorded in 8 other groups: Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.24086e-06; MAF= 0.00012%, 2/1611782 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 1.6021e-05; MAF= 0.00160%, 1/62418 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
SpliceAI and Pangolin
SpliceAI acceptor lossat -340 bp
0.000
SpliceAI acceptor gainat +4 bp
0.019
SpliceAI donor lossat -100 bp
0.000
SpliceAI donor gainat -72 bp
0.011
Pangolin splice lossmagnitude shown
-0.028
Pangolin splice gain
0.024
Other predictors
REVEL
0.599
BayesDel
0.054
How the predictions were used
PP3Not met: missense REVEL score 0.599 is below the supporting PP3 threshold of >=0.644.
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Reasoning
The variant is a missense substitution, so PP3/BP4 must use the missense protein-impact path only. The ENIGMA BRCA1 specification was consulted first, and no variant-level pre-assigned PP3 code was found for c.598G>A, p.Gly200Arg, or p.G200R in SupplementaryTables_V1.2_2024-11-18.xlsx, Specifications_V1.2_2024-11-18.docx, Appendices_V1.2_2024-11-18.docx, or PMID_22505045_Houdayer_2012_HumMutat.pdf. The REVEL score is 0.599, below the supplied ClinGen SVI supporting PP3 threshold of >=0.644 (Pejaver et al. 2022, PMID:36413997), so PP3 is not met. SpliceAI and BayesDel were not used to substitute for the applicable missense REVEL path.
Rule
Missense variant: use the REVEL path only; supporting PP3 requires REVEL >=0.644 when no governing VCEP variant-level pre-assigned code applies.
Evidence considered
The case normalization identifies NM_007294.4:c.598G>A as the missense variant NP_009225.1:p.(Gly200Arg), also p.(G200R).
The ENIGMA BRCA1 v1.2 specification was the governing framework; its PP3 rule was reviewed before applying the supplied generic missense calibration.
The recorded REVEL score is 0.599. The supplied ClinGen SVI calibration defines supporting PP3 at REVEL >=0.644 (Pejaver et al. 2022, PMID:36413997).
Exact searches for c.598G>A, p.Gly200Arg, and p.G200R found no variant-level pre-assigned PP3 entry in the four governing full-text files named in gaps_remaining.
Still missing
No variant-level pre-assigned PP3 entry for c.598G>A, p.Gly200Arg, or p.G200R was found in SupplementaryTables_V1.2_2024-11-18.xlsx.
No variant-level pre-assigned PP3 entry for c.598G>A, p.Gly200Arg, or p.G200R was found in Specifications_V1.2_2024-11-18.docx.
No variant-level pre-assigned PP3 entry for c.598G>A, p.Gly200Arg, or p.G200R was found in Appendices_V1.2_2024-11-18.docx.
No variant-level pre-assigned PP3 entry for c.598G>A, p.Gly200Arg, or p.G200R was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.
BP4Not met: missense REVEL score 0.599 exceeds the supporting BP4 threshold of <=0.29 and is gray-zone.
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Reasoning
The variant is a missense substitution, so PP3/BP4 must use the missense protein-impact path only. The ENIGMA BRCA1 specification was consulted first, and no variant-level pre-assigned BP4 code was found for c.598G>A, p.Gly200Arg, or p.G200R in SupplementaryTables_V1.2_2024-11-18.xlsx, Specifications_V1.2_2024-11-18.docx, Appendices_V1.2_2024-11-18.docx, or PMID_22505045_Houdayer_2012_HumMutat.pdf. The REVEL score is 0.599, above the supplied ClinGen SVI supporting BP4 threshold of <=0.29 and within the gray zone, so BP4 is not met. The SpliceAI score and BayesDel score were not used to substitute for the applicable missense REVEL path.
Rule
Missense variant: use the REVEL path only; supporting BP4 requires REVEL <=0.29 when no governing VCEP variant-level pre-assigned code applies. Gray-zone REVEL does not permit substitution of SpliceAI.
Evidence considered
The case normalization identifies NM_007294.4:c.598G>A as the missense variant NP_009225.1:p.(Gly200Arg), also p.(G200R).
The ENIGMA BRCA1 v1.2 specification was the governing framework; its BP4 rule was reviewed before applying the supplied generic missense calibration.
The recorded REVEL score is 0.599. The supplied ClinGen SVI calibration defines supporting BP4 at REVEL <=0.29 and does not support BP4 in the gray zone above that threshold (Pejaver et al. 2022, PMID:36413997).
Exact searches for c.598G>A, p.Gly200Arg, and p.G200R found no variant-level pre-assigned BP4 entry in the four governing full-text files named in gaps_remaining.
Still missing
No variant-level pre-assigned BP4 entry for c.598G>A, p.Gly200Arg, or p.G200R was found in SupplementaryTables_V1.2_2024-11-18.xlsx.
No variant-level pre-assigned BP4 entry for c.598G>A, p.Gly200Arg, or p.G200R was found in Specifications_V1.2_2024-11-18.docx.
No variant-level pre-assigned BP4 entry for c.598G>A, p.Gly200Arg, or p.G200R was found in Appendices_V1.2_2024-11-18.docx.
No variant-level pre-assigned BP4 entry for c.598G>A, p.Gly200Arg, or p.G200R was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.
BP7N/ANot applicable: p.Gly200Arg is a missense change, whereas BP7 applies only to synonymous variants.
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Reasoning
BP7 applies only to synonymous variants. This variant is missense, NM_007294.4:c.598G>A, p.(Gly200Arg), so BP7 is out of scope and no predictor evaluation is applicable.
Rule
BP7 applies only to synonymous variants; this missense variant is not_applicable.
Evidence considered
The case normalization identifies NM_007294.4:c.598G>A as the missense variant NP_009225.1:p.(Gly200Arg), also p.(G200R).
The ENIGMA BRCA1 v1.2 framework limits BP7 to synonymous or specified noncoding contexts; a missense variant is outside BP7 scope.
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.24086e-06; MAF= 0.00012%, 2/1611782 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 1.6021e-05; MAF= 0.00160%, 1/62418 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.599. BayesDel score = 0.0537567.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. BRCA1, a tumor suppressor involved in the DNA damage response, is mutated in various cancer types.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV58798374, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
This variant was interpreted by pipeline 8.0.0.
The current version is 11.0.07.
Re-running queues a fresh interpretation; the result replaces this page when complete.
Re-runs are not free. Blank draws on today's public interpretation allowance; with a code, it uses one of that code's uses.