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.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
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.
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 1
BP1Strong
BP1 · strong
Met at Strong: residue 1001 is outside approved domains and SpliceAI max delta 0.004 meets the ≤0.1 no-splicing requirement.
Recorded classification: Uncertain significance
VUS: BP1 (strong) is the only met criterion, with no qualifying pathogenic evidence or additional benign evidence to satisfy ENIGMA's combination rules.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
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 · 4 not met · 10 not assessed · 13 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
All three requested consequence/LOF criteria are not applicable under the ENIGMA BRCA1/2 VCEP v1.2 rules because the variant is a missense substitution and PM4/BP3 are explicitly not to be used.
For the requested codon, residue, and domain criteria, the VCEP-specific result is BP1_Strong met; PS1 is not met because no qualifying same-amino-acid pathogenic comparator was identified; PM1, PM5, and PP2 are not applicable under explicit ENIGMA rules.
The variant's residue 1001 was checked against all three VCEP-approved BRCA1 functional-domain intervals, and the maximum SpliceAI delta score was 0.004.
PS2 and PM6 are not applicable because the VCEP explicitly prohibits their use.
PP1 and BS4 remain not assessed because no quantitative segregation or non-segregation evidence is available.
For this group, the governing ENIGMA VCEP text makes PP5 and BP6 not applicable, while PS4, PP4, and BP5 require specific evidence that is not available for this variant.
The requested variant notations were searched in the governing VCEP full-text directory; no exact variant entry was found in the listed files.
Only PP3, BP4, and BP7 were evaluated under the ClinGen ENIGMA BRCA1/2 VCEP specification v1.2.
PP3 is not met because the applicable missense splice path requires SpliceAI ≥0.2 and the maximum delta score is 0.004; BP4 and BP7 are not applicable to this missense variant under their own scope rules.
Population data show absence from the ENIGMA-specified gnomAD non-cancer datasets, but no benign population criterion is met and PM2 remains unassessed because the required regional read depth is not documented.
BS2 is unassessed because no healthy-adult observations or ENIGMA Table 8 point calculation are available.
No criteria match.
Met · 1
BP1StrongVCEPMet at Strong: residue 1001 is outside approved domains and SpliceAI max delta 0.004 meets the ≤0.1 no-splicing requirement.
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Reasoning
The variant is a missense substitution at residue 1001. The VCEP-approved critical functional domains are RING aa 2-101, coiled-coil aa 1391-1424, and BRCT repeats aa 1650-1857; residue 1001 is outside all of them. SpliceAI maximum delta is 0.004, satisfying the VCEP requirement of ≤0.1 for no predicted splicing. Therefore BP1_Strong is met; the VCEP states that missense prediction is not applicable on this path.
VCEP rule
Apply BP1_Strong for silent substitution, missense or in-frame insertion, deletion or delins variants outside a (potentially) clinically important functional domain ... AND ... no splicing predicted (SpliceAI ≤0.1). ... Missense prediction not applicable.
Evidence considered
Specifications v1.2, BP1_Strong rule: applies to missense variants outside a potentially clinically important functional domain with no predicted splicing (SpliceAI ≤0.1); missense prediction is not applicable.
Approved BRCA1 domains checked: RING aa 2-101, coiled-coil aa 1391-1424, and BRCT repeats aa 1650-1857; p.Glu1001Lys at aa 1001 is outside every listed domain.
SpliceAI case result: DS_AG 0.004, DS_AL 0.000, DS_DG 0.000, DS_DL 0.001; maximum delta score 0.004.
PS1VCEPNot met: no VCEP-recorded pathogenic or likely pathogenic variant was identified with the same p.Glu1001Lys amino-acid substitution.
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Reasoning
The variant is a predicted missense substitution, and SpliceAI is 0.004, satisfying the VCEP's no-predicted-splicing condition. However, the consulted ENIGMA VCEP files contain no entry for c.3001G>A, p.Glu1001Lys, or p.E1001K and no previously classified pathogenic or likely pathogenic variant producing the same amino-acid substitution was identified. Therefore the VCEP prerequisite for PS1 is not met.
VCEP rule
Apply PS1, for predicted missense substitutions, where a previously classified pathogenic variant is considered to act via protein change (no confirmed or predicted effect on mRNA splicing (SpliceAI≤0.1)). ... Apply PS1_Moderate, for predicted missense substitutions, where previously established likely pathogenic variant is considered to act via protein change (no confirmed or predicted effect on mRNA splicing (SpliceAI≤0.1)).
Evidence considered
Case normalization: NM_007294.4:c.3001G>A produces NP_009225.1:p.(Glu1001Lys), p.(E1001K), a missense substitution.
SpliceAI result: maximum delta score 0.004, below the VCEP PS1 no-splicing threshold of 0.1.
The four governing ENIGMA full-text files were searched for c.3001G>A, p.Glu1001Lys, and p.E1001K; no matching variant entry or same-amino-acid pathogenic comparator was found.
Still missing
No matching c.3001G>A, p.Glu1001Lys, or p.E1001K entry was found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt.
No matching c.3001G>A, p.Glu1001Lys, or p.E1001K entry was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
No matching c.3001G>A, p.Glu1001Lys, or p.E1001K entry was found in Specifications_V1.2_2024-11-18.docx.txt.
No matching c.3001G>A, p.Glu1001Lys, or p.E1001K entry was found in Appendices_V1.2_2024-11-18.docx.txt.
PP3VCEPNot met: SpliceAI maximum delta 0.004 is below the VCEP PP3 splice threshold of ≥0.2 for this missense variant.
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Reasoning
The variant is a missense substitution, p.(Glu1001Lys), outside the VCEP-defined BRCA1 clinically important domains (RING aa 2-101, coiled-coil aa 1391-1424, BRCT repeats aa 1650-1857). Therefore the PP3 protein-impact path does not apply. The VCEP's splice-prediction path does apply to missense variants irrespective of domain location, but requires SpliceAI ≥0.2; the case SpliceAI maximum delta score is 0.004, so PP3 is not met. No exact c.3001G>A, p.Glu1001Lys, or p.E1001K entry was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt, Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, or PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
VCEP rule
Do not apply PP3 if PVS1 is met at any strength. ... Apply PP3 for missense or in-frame insertion, deletion or delins variants inside a (potentially) clinically important functional domain and predicted impact via protein change (BayesDel predicted Impact). ... Apply PP3 for predicted splicing (SpliceAI ≥0.2) for silent, missense/in-frame (irrespective of location in clinically important functional domain) and for intronic variants outside of the donor and acceptor ±1,2 positions.
Evidence considered
The VCEP CSPEC rule identifies the variant as a missense substitution and permits the splice-prediction path irrespective of functional-domain location, requiring SpliceAI ≥0.2.
SpliceAI result for NM_007294.4:c.3001G>A: DS_AG 0.004, DS_AL 0.000, DS_DG 0.000, DS_DL 0.001; maximum delta score 0.004.
The VCEP-defined clinically important BRCA1 domains are RING aa 2-101, coiled-coil aa 1391-1424, and BRCT repeats aa 1650-1857; p.Glu1001Lys is outside these domains.
Exact-notation searches for c.3001G>A, p.Glu1001Lys, and p.E1001K found no entry in the four governing full-text files named for this case.
Still missing
No exact c.3001G>A, p.Glu1001Lys, or p.E1001K entry found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
No exact c.3001G>A, p.Glu1001Lys, or p.E1001K entry found in Specifications_V1.2_2024-11-18.docx.txt.
No exact c.3001G>A, p.Glu1001Lys, or p.E1001K entry found in Appendices_V1.2_2024-11-18.docx.txt.
No exact c.3001G>A, p.Glu1001Lys, or p.E1001K entry found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
BA1VCEPNot met: the qualifying gnomAD non-cancer datasets report no variant, so no filter allele frequency exceeds the ENIGMA BA1 threshold of 0.001.
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Reasoning
The ENIGMA BRCA1 specification assigns BA1 when the maximum filter allele frequency exceeds 0.1% (FAF >0.001) in a qualifying non-founder gnomAD population, with adequate read depth and no applicable founder-variant exclusion. The required gnomAD v2.1 non-cancer exome and gnomAD v3.1 non-cancer genome records for NM_007294.4:c.3001G>A (p.Glu1001Lys; p.E1001K) are absent, so no qualifying FAF above 0.001 is present and BA1 is not met. The variant was not found in SupplementaryTables_V1.2_2024-11-18.xlsx, Specifications_V1.2_2024-11-18.docx, Appendices_V1.2_2024-11-18.docx, or HUMU-40-1557-s001.xlsx when searched under all three requested notations.
VCEP rule
Above 0.001 (0.1%) ... Apply based on maximum filter allele frequency observed in a gnomAD non-founder population, considering exome and genome data separately.
Evidence considered
ENIGMA BRCA1 specification, BA1 rule: maximum filter allele frequency must be above 0.001 (0.1%) in gnomAD v2.1 non-cancer exomes and/or gnomAD v3.1 non-cancer genomes, using non-founder populations.
GNOMAD_V2_1_NON_CANCER: NM_007294.4:c.3001G>A / p.Glu1001Lys / p.E1001K absent; no FAF reported.
GNOMAD_V3_1_NON_CANCER: NM_007294.4:c.3001G>A / p.Glu1001Lys / p.E1001K absent; no FAF reported.
Variant-notation search found no matching entry in SupplementaryTables_V1.2_2024-11-18.xlsx.txt, Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, or HUMU-40-1557-s001.xlsx.txt.
BS1VCEPNot met: the qualifying gnomAD non-cancer datasets report no variant, so no filter allele frequency exceeds the ENIGMA BS1 threshold of 0.00002.
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Reasoning
The ENIGMA BRCA1 specification assigns BS1 Strong when FAF is above 0.01% (FAF >0.0001), and BS1 Supporting when FAF is above 0.002% and less than or equal to 0.01% (FAF >0.00002 and <=0.0001), in the specified non-founder gnomAD non-cancer datasets. The required gnomAD v2.1 non-cancer exome and gnomAD v3.1 non-cancer genome records are absent for NM_007294.4:c.3001G>A (p.Glu1001Lys; p.E1001K), so no qualifying FAF is available above either BS1 threshold. The variant was not found in SupplementaryTables_V1.2_2024-11-18.xlsx, Specifications_V1.2_2024-11-18.docx, Appendices_V1.2_2024-11-18.docx, or HUMU-40-1557-s001.xlsx when searched under all three requested notations.
VCEP rule
BS1 - above 0.0001 (0.01%) BS1_Supporting - >0.00002 (0.002%) to <= 0.0001 (0.01%). ... Apply based on maximum filter allele frequency in a gnomAD non-founder population, considering exome and genome data separately.
GNOMAD_V2_1_NON_CANCER: NM_007294.4:c.3001G>A / p.Glu1001Lys / p.E1001K absent; no FAF reported.
GNOMAD_V3_1_NON_CANCER: NM_007294.4:c.3001G>A / p.Glu1001Lys / p.E1001K absent; no FAF reported.
Variant-notation search found no matching entry in SupplementaryTables_V1.2_2024-11-18.xlsx.txt, Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, or HUMU-40-1557-s001.xlsx.txt.
PS3VCEPNot assessed: no exact c.3001G>A, p.Glu1001Lys, or p.E1001K entry was found in the governing functional tables.
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Reasoning
The ENIGMA BRCA1 functional-assay evidence was checked using all three variant notations (c.3001G>A, p.Glu1001Lys, and p.E1001K). No exact variant entry was found in Specifications Table 9, Supplementary Tables ST4, or HUMU-40-1557-s001. The governing VCEP rule requires well-established functional studies showing a damaging effect and directs reviewers to Table 9 for calibrated code recommendations; without a variant-specific calibrated assay result, PS3 cannot be assigned. The full Specifications and Appendices were also searched for the variant and did not contain a variant-specific functional result.
Evidence considered
ClinGen ENIGMA BRCA1/2 CSPEC PS3 rule: well-established in vitro or in vivo functional studies supportive of a damaging effect, with protein-only or combined mRNA-and-protein assays, and calibrated recommendations in Specifications Table 9.
Specifications_Table9_V1.2_2024-11-18.xlsx.txt: searched c.3001G>A, p.Glu1001Lys, and p.E1001K; no exact variant row found.
SupplementaryTables_V1.2_2024-11-18.xlsx.txt, including ST4: searched c.3001G>A, p.Glu1001Lys, and p.E1001K; no exact variant row found.
HUMU-40-1557-s001.xlsx.txt: searched c.3001G>A, p.Glu1001Lys, and p.E1001K; no exact variant row found.
Specifications_V1.2_2024-11-18.docx.txt and Appendices_V1.2_2024-11-18.docx.txt: searched all three variant notations; no variant-specific functional result found.
Still missing
No exact c.3001G>A, p.Glu1001Lys, or p.E1001K entry in Specifications_Table9_V1.2_2024-11-18.xlsx.txt.
No exact c.3001G>A, p.Glu1001Lys, or p.E1001K entry in SupplementaryTables_V1.2_2024-11-18.xlsx.txt, including the ST4 functional assay dataset.
No exact c.3001G>A, p.Glu1001Lys, or p.E1001K entry in HUMU-40-1557-s001.xlsx.txt.
No exact c.3001G>A, p.Glu1001Lys, or p.E1001K entry in Specifications_V1.2_2024-11-18.docx.txt or Appendices_V1.2_2024-11-18.docx.txt.
PS4VCEPNot assessed: no variant-specific case-control odds ratio, p-value, or confidence interval is available for the required PS4 comparison.
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Reasoning
The ENIGMA rule requires a matched case-control study with p-value ≤0.05, OR ≥4, and a lower confidence interval excluding 2.0. The available case evidence contains no variant-specific case-control counts, odds ratio, p-value, or confidence interval for NM_007294.4:c.3001G>A (p.Glu1001Lys), so PS4 cannot be evaluated without substituting non-governing evidence.
VCEP rule
Case-control studies; p-value ≤0.05 and OR ≥4 (lower confidence interval excludes 2.0).
Evidence considered
ENIGMA CSPEC PS4 rule: case-control studies require p-value ≤0.05 and OR ≥4, with the lower confidence interval excluding 2.0.
The available case evidence does not provide a variant-specific case-control OR, p-value, or confidence interval for c.3001G>A / p.Glu1001Lys.
The ONCOKB and ClinVar records do not supply a matched case-control enrichment dataset for this variant.
Still missing
No variant-specific case-control OR, p-value, or confidence interval was found in the available evidence for NM_007294.4:c.3001G>A (p.Glu1001Lys).
PMID_31853058_BRCA1_clinical_history_LR.xlsx was searched for c.3001G>A, p.Glu1001Lys, and p.E1001K; no entry was found. This file is a clinical-history LR table and does not provide PS4 case-control evidence.
PM2VCEPNot assessed: the variant is absent from required gnomAD non-cancer datasets, but regional average read depth of at least 25 is not documented.
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Reasoning
The ENIGMA BRCA1 PM2 Supporting rule requires absence from the specified outbred gnomAD controls and an average read depth of at least 25 around the variant. NM_007294.4:c.3001G>A (p.Glu1001Lys; p.E1001K) is absent from the gnomAD v2.1 non-cancer exome and gnomAD v3.1 non-cancer genome records, but the case evidence does not provide the required regional average read depth or quality-control result. PM2 therefore cannot be applied without that prerequisite. The variant was not found in SupplementaryTables_V1.2_2024-11-18.xlsx, Specifications_V1.2_2024-11-18.docx, Appendices_V1.2_2024-11-18.docx, or HUMU-40-1557-s001.xlsx when searched under all three requested notations.
VCEP rule
Absent from gnomAD (exome and genome). ... Observation of a variant only once in a gnomAD outbred population is not informative (no code applied). Do not apply for insertion, deletion or delins variants. Do not apply if read depth <25 at region around the variant.
Evidence considered
ENIGMA BRCA1 specification, PM2 Supporting rule: absence from gnomAD v2.1 non-cancer exome and gnomAD v3.1 non-cancer genome controls is required, and the region around the variant must have average read depth >=25.
PM3VCEPNot assessed: no documented same-gene pathogenic/likely pathogenic co-occurring variant, phase, or Fanconi Anemia phenotype is available to assign the VCEP's PM3 points.
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Reasoning
The ENIGMA BRCA1 VCEP PM3 rule requires a patient with a phenotype consistent with BRCA1-related Fanconi Anemia and a co-occurring variant in the same gene. The available case evidence does not document a pathogenic or likely pathogenic BRCA1 co-occurring variant, phase or homozygosity, Fanconi Anemia chromosome-breakage testing, the required Fanconi Anemia clinical features, or PM3-related points. Therefore PM3 cannot be assigned or weighted from the available evidence. Searches of Specifications_V1.2_2024-11-18.docx.txt for c.3001G>A, p.Glu1001Lys, and p.E1001K found no variant-specific entry.
VCEP rule
Apply for patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia (FA), and co-occurrent variants in the same gene. ... Phenotype is considered consistent with BRCA1- or BRCA2-related FA if: ... (i) Increased chromosome breakage (DEB, MMC, or spontaneous) and at least one clinical feature indicative of BRCA1/2-related FA, categorized under: physical features, pathology and laboratory findings, cancer diagnosis ≤5yr. ... (ii) Result unknown for chromosome breakage, and at least two clinical features indicative of BRCA1/2-related FA under at least two of the three categories: physical features, pathology and laboratory findings, cancer diagnosis ≤5yr. ... See Table 6 for approach to assign points per proband, and final PM3 code assignment based on the sum of PM3-related points. ... For related individuals score only most severe presentation.
Evidence considered
case evidence for NM_007294.4:c.3001G>A / p.(Glu1001Lys) contains no documented same-gene pathogenic or likely pathogenic co-occurring variant, phase or homozygosity, Fanconi Anemia phenotype, chromosome-breakage result, or PM3-related point count
Specifications_V1.2_2024-11-18.docx.txt, Table 1 PM3_VariableWeight rule and Table 6 PM3-related points: PM3 requires BRCA1/2-related Fanconi Anemia phenotype with co-occurring variants in the same gene and assigns PM3 from summed points
Specifications_V1.2_2024-11-18.docx.txt searched for c.3001G>A, p.Glu1001Lys, and p.E1001K; no variant-specific entry was found
Still missing
No documented pathogenic or likely pathogenic BRCA1 co-occurring variant, phase or homozygosity, Fanconi Anemia phenotype, chromosome-breakage result, or PM3 point count in the available case evidence.
No entry for c.3001G>A, p.Glu1001Lys, or p.E1001K was found when Specifications_V1.2_2024-11-18.docx.txt was searched.
PP1VCEPNot assessed: no quantitative cosegregation LR or affected-family genotype data are available to compare with the VCEP PP1 threshold of LR ≥2.08:1.
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Reasoning
No quantitative cosegregation likelihood ratio, pedigree, affected-relative genotype data, or meioses are available for NM_007294.4:c.3001G>A. The case bundle contains no usable segregation evidence, and searches of Specifications_V1.2_2024-11-18.docx.txt and HUMU-40-1557-s001.xlsx.txt found no entry for c.3001G>A, p.Glu1001Lys, or p.E1001K. Therefore the VCEP PP1 LR thresholds cannot be evaluated.
VCEP rule
Co-segregation with disease in multiple affected family members ... Apply weight as per Bayes Score: ... PP1 - LR ≥2.08:1 ... PP1_Moderate – LR≥4.3:1 ... PP1_Strong – LR≥18.7:1 ... PP1_Very Strong – LR≥350:1
Evidence considered
Specifications_V1.2_2024-11-18.docx, PP1 entry: requires co-segregation with disease in multiple affected family members measured by a quantitative co-segregation analysis method, with strength assigned by Bayes Score.
No case-level pedigree, affected-relative genotype, meiosis, or quantitative LR evidence was present for this variant.
Still missing
No quantitative cosegregation LR, pedigree, affected-relative genotype data, or meioses were provided.
No entry for c.3001G>A, p.Glu1001Lys, or p.E1001K was found in Specifications_V1.2_2024-11-18.docx.txt.
No entry for c.3001G>A, p.Glu1001Lys, or p.E1001K was found in HUMU-40-1557-s001.xlsx.txt.
PP4VCEPNot assessed: no combined clinical likelihood ratio is available, and the Li et al. table has no matching c.3001G>A row.
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Reasoning
ENIGMA restricts PP4 to a combined likelihood ratio from multifactorial clinical data. No combined clinical LR or complete component LRs for this variant were available. The Li et al. BRCA1 clinical-history table was searched for c.3001G>A, p.Glu1001Lys, and p.E1001K and contained no matching row; therefore no PP4 strength can be assigned.
VCEP rule
Breast cancer is very common and has a high degree of genetic heterogeneity (caused by pathogenic variants in numerous genes). Use ONLY to capture combined LR towards pathogenicity, based on multifactorial likelihood clinical data. ... PP4 - LR ≥2.08:1 ... PP4_Moderate – LR≥4.3:1 ... PP4_Strong – LR ≥18.7:1 ... PP4_Very Strong – LR ≥350:1
Evidence considered
ENIGMA PP4 rule: use only combined LR from multifactorial likelihood clinical data; PP4 Supporting requires LR ≥2.08:1, Moderate ≥4.3:1, Strong ≥18.7:1, and Very Strong ≥350:1.
PMID_31853058_BRCA1_clinical_history_LR.xlsx was searched across the requested c. and protein notations; no matching BRCA1 row was found.
Easton et al. 2007 was consulted as methodology/context only; no variant-specific combined LR for c.3001G>A was available.
Still missing
No combined multifactorial clinical LR or complete clinical LR components were found for this variant.
PMID_31853058_BRCA1_clinical_history_LR.xlsx was searched for c.3001G>A, p.Glu1001Lys, and p.E1001K; no entry was found.
The available Easton and Li paper materials provide methodology but no variant-specific combined LR for this variant.
BS2Not assessed: no healthy-adult genotype observations or ENIGMA BS2 point count is available to reach the required threshold of 1, 2, or 4 points.
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Reasoning
The ENIGMA BRCA1 BS2 rule requires point-based observations in healthy adults and stipulates application in the absence of Fanconi Anemia features. The available case evidence contains no healthy-adult genotype observations, zygosity or homozygote counts, proband-level BS2 points, or Fanconi Anemia phenotype assessment; population absence cannot substitute for BS2. Therefore BS2 cannot be assessed.
Evidence considered
ENIGMA BRCA1 specification: BS2 is a point-based criterion for healthy-adult observations, applied in the absence of Fanconi Anemia features; no qualifying observations or point tally are present in the case evidence.
Still missing
Healthy-adult observations with genotype and zygosity are unavailable.
The ENIGMA Specifications Table 8 point calculation cannot be performed from the available evidence.
Fanconi Anemia phenotype status is not documented.
BS3VCEPNot assessed: no exact c.3001G>A, p.Glu1001Lys, or p.E1001K entry was found in the governing functional tables.
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Reasoning
The ENIGMA BRCA1 functional-assay evidence was checked using all three variant notations (c.3001G>A, p.Glu1001Lys, and p.E1001K). No exact variant entry was found in Specifications Table 9, Supplementary Tables ST4, or HUMU-40-1557-s001. The governing VCEP rule requires well-established functional studies showing no damaging effect on protein function and directs reviewers to Table 9 for calibrated code recommendations; without a variant-specific calibrated assay result, BS3 cannot be assigned. The full Specifications and Appendices were also searched for the variant and did not contain a variant-specific functional result.
Evidence considered
ClinGen ENIGMA BRCA1/2 CSPEC BS3 rule: well-established in vitro or in vivo functional studies showing no damaging effect on protein function, with protein-only or combined mRNA-and-protein assays, and calibrated recommendations in Specifications Table 9.
Specifications_Table9_V1.2_2024-11-18.xlsx.txt: searched c.3001G>A, p.Glu1001Lys, and p.E1001K; no exact variant row found.
SupplementaryTables_V1.2_2024-11-18.xlsx.txt, including ST4: searched c.3001G>A, p.Glu1001Lys, and p.E1001K; no exact variant row found.
HUMU-40-1557-s001.xlsx.txt: searched c.3001G>A, p.Glu1001Lys, and p.E1001K; no exact variant row found.
Specifications_V1.2_2024-11-18.docx.txt and Appendices_V1.2_2024-11-18.docx.txt: searched all three variant notations; no variant-specific functional result found.
Still missing
No exact c.3001G>A, p.Glu1001Lys, or p.E1001K entry in Specifications_Table9_V1.2_2024-11-18.xlsx.txt.
No exact c.3001G>A, p.Glu1001Lys, or p.E1001K entry in SupplementaryTables_V1.2_2024-11-18.xlsx.txt, including the ST4 functional assay dataset.
No exact c.3001G>A, p.Glu1001Lys, or p.E1001K entry in HUMU-40-1557-s001.xlsx.txt.
No exact c.3001G>A, p.Glu1001Lys, or p.E1001K entry in Specifications_V1.2_2024-11-18.docx.txt or Appendices_V1.2_2024-11-18.docx.txt.
BS4VCEPNot assessed: no quantitative negative-cosegregation LR or affected-family genotype data are available to compare with the VCEP BS4 threshold of LR ≤0.48:1.
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Reasoning
No quantitative negative-cosegregation likelihood ratio, pedigree, affected-relative genotype data, or meioses are available for NM_007294.4:c.3001G>A. The case bundle contains no usable non-segregation evidence, and searches of Specifications_V1.2_2024-11-18.docx.txt and HUMU-40-1557-s001.xlsx.txt found no entry for c.3001G>A, p.Glu1001Lys, or p.E1001K. Therefore the VCEP BS4 LR thresholds cannot be evaluated.
VCEP rule
Lack of segregation in affected members of a family. ... Apply weight as per Bayes Score: ... BS4_Supporting - LR ≤0.48 to >0.23:1 ... BS4_Moderate - LR ≤0.23:1 ... BS4 - LR ≤0.05:1 ... BS4_Very strong – LR ≤0.00285:1
Evidence considered
Specifications_V1.2_2024-11-18.docx, BS4 entry: requires lack of segregation in affected family members measured by a quantitative co-segregation analysis method, with strength assigned by Bayes Score.
No case-level pedigree, affected-relative genotype, meiosis, or quantitative LR evidence was present for this variant.
Still missing
No quantitative negative-cosegregation LR, pedigree, affected-relative genotype data, or meioses were provided.
No entry for c.3001G>A, p.Glu1001Lys, or p.E1001K was found in Specifications_V1.2_2024-11-18.docx.txt.
No entry for c.3001G>A, p.Glu1001Lys, or p.E1001K was found in HUMU-40-1557-s001.xlsx.txt.
BP5VCEPNot assessed: no combined clinical likelihood ratio is available, and the Li et al. table has no matching c.3001G>A row.
Details ▾Hide ▴
Reasoning
ENIGMA restricts BP5 to a combined likelihood ratio against pathogenicity from multifactorial clinical data. No combined clinical LR or complete component LRs for this variant were available. The Li et al. BRCA1 clinical-history table was searched for c.3001G>A, p.Glu1001Lys, and p.E1001K and contained no matching row, so the criterion cannot be assessed.
VCEP rule
Use ONLY to capture combined LR against pathogenicity, based on multifactorial likelihood clinical data. ... BP5_VeryStrong – LR ≤0.00285:1 ... BP5_Strong - LR ≤0.05:1 ... BP5_Moderate - LR ≤0.23:1 ... BP5 - LR ≤0.48 to >0.23:1
Evidence considered
ENIGMA BP5 rule: use only combined LR against pathogenicity from multifactorial likelihood clinical data; BP5 Supporting requires LR ≤0.48:1, Moderate ≤0.23:1, Strong ≤0.05:1, and Very Strong ≤0.00285:1.
The required direction is downward: no variant-specific LR is available to test an inequality such as LR ≤0.48.
PMID_31853058_BRCA1_clinical_history_LR.xlsx was searched across the requested c. and protein notations; no matching BRCA1 row was found.
Still missing
No combined multifactorial clinical LR or complete clinical LR components were found for this variant.
PMID_31853058_BRCA1_clinical_history_LR.xlsx was searched for c.3001G>A, p.Glu1001Lys, and p.E1001K; no entry was found.
The available Easton and Li paper materials provide methodology but no variant-specific combined LR against pathogenicity for this variant.
Not applicable · 13· recorded as not applicableShow reasons ▾Hide reasons ▴PVS1N/ANot applicable: c.3001G>A is a missense substitution, whereas ENIGMA PVS1 is limited to specified null variants such as nonsense, frameshift, splice-site, and exon-deletion variants.
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Reasoning
The variant is NM_007294.4:c.3001G>A, NP_009225.1:p.(Glu1001Lys) (p.(E1001K)), and the case evidence identifies it as a missense substitution. The ENIGMA PVS1 rule is limited to null variants, specifically nonsense, frameshift, canonical donor/acceptor +/-1,2 splice-site, initiation-codon, or single/multi-exon deletion variants; this missense variant is none of those. SpliceAI max delta is 0.004, but the PVS1 rule does not apply to a missense protein substitution on that basis. The required VCEP files were searched for c.3001G>A, p.Glu1001Lys, and p.E1001K: no variant-level entry was found in Specifications_Table4_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.
VCEP rule
Null variant (nonsense, frameshift, splice site (donor/acceptor +/−1,2), initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
Case splice evidence: SpliceAI max delta score = 0.004.
Specifications_V1.2_2024-11-18.docx, Table 1, PVS1: null variants are nonsense, frameshift, canonical donor/acceptor +/-1,2 splice-site, initiation-codon, or single/multi-exon deletion variants, with strength assigned according to the PVS1 flowchart.
Specifications_Table4_V1.2_2024-11-18.xlsx: searched the BRCA1 exon-level PVS1 decision table under c.3001G>A, p.Glu1001Lys, and p.E1001K; no matching row was found.
Still missing
No c.3001G>A, p.Glu1001Lys, or p.E1001K entry was found in Specifications_Table4_V1.2_2024-11-18.xlsx.
No c.3001G>A, p.Glu1001Lys, or p.E1001K entry was found in Specifications_V1.2_2024-11-18.docx.
No c.3001G>A, p.Glu1001Lys, or p.E1001K entry was found in Appendices_V1.2_2024-11-18.docx.
No c.3001G>A, p.Glu1001Lys, or p.E1001K entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.
PS2VCEPNot applicable: the ENIGMA specification explicitly says not to use PS2 because de novo occurrences lack calibrated predictive value.
Details ▾Hide ▴
Reasoning
The ENIGMA BRCA1 Version 1.2 specification explicitly says not to use PS2 because BRCA1/2-related cancers occur relatively commonly and there is no information to calibrate the predictive capacity of de novo occurrences.
VCEP rule
De novo (paternity confirmed) in a patient with the disease and no family history. ... Do not use ... BRCA1/2-related cancers occur relatively commonly. No information to calibrate the predictive capacity of de novo occurrences.
Evidence considered
Specifications_V1.2_2024-11-18.docx, PS2 entry: the criterion is marked "Do not use" because BRCA1/2-related cancers occur relatively commonly and de novo predictive capacity is not calibrated.
PM1VCEPNot applicable: ENIGMA explicitly says PM1 is not used, regardless of this residue's location outside its listed critical domains.
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Reasoning
The ENIGMA BRCA1 VCEP explicitly directs that PM1 is not used and that hotspot or critical-domain information is considered as part of PP3/BP4 instead. The variant is at residue 1001, outside the VCEP-listed RING aa 2-101, coiled-coil aa 1391-1424, and BRCT repeats aa 1650-1857 domains, but that location does not change the explicit PM1 applicability decision.
VCEP rule
Located in a mutational hot spot and/or critical and well-established functional domain. ... Do not use ... Considered as component of bioinformatic analysis (PP3/BP4).
Evidence considered
Specifications v1.2, Table 1 PM1 entry: PM1 is marked 'Do not use' and is considered as a component of PP3/BP4.
ENIGMA domain definition: BRCA1 RING aa 2-101, coiled-coil aa 1391-1424, and BRCA1 BRCT repeats aa 1650-1857; residue 1001 is outside all three.
Appendix C Table 3 lists BRCA1 domain intervals and clinically important residues; no p.E1001K entry is present.
PM4VCEPNot applicable: p.(Glu1001Lys) is a missense substitution with no protein-length change, and ENIGMA explicitly says PM4 is not to be used.
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Reasoning
The variant is a missense substitution, not an in-frame deletion/insertion or stop-loss variant, and therefore does not produce a VCEP-defined protein length change. ENIGMA BRCA1/2 v1.2 explicitly marks PM4 as not to be used and states that it is considered as a component of bioinformatic analysis. The required VCEP files were searched for c.3001G>A, p.Glu1001Lys, and p.E1001K: no variant-level entry was found in Specifications_Table4_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.
VCEP rule
Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants. ... Do not use ... Considered as component of bioinformatic analysis (PP3/BP4).
Evidence considered
Case variant assessment: NM_007294.4:c.3001G>A; NP_009225.1:p.(Glu1001Lys) / p.(E1001K); consequence_class = missense.
Specifications_V1.2_2024-11-18.docx, Table 1, PM4: protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants; PM4 is marked 'Do not use' and considered as a component of bioinformatic analysis.
Still missing
No c.3001G>A, p.Glu1001Lys, or p.E1001K entry was found in Specifications_Table4_V1.2_2024-11-18.xlsx.
No c.3001G>A, p.Glu1001Lys, or p.E1001K entry was found in Specifications_V1.2_2024-11-18.docx.
No c.3001G>A, p.Glu1001Lys, or p.E1001K entry was found in Appendices_V1.2_2024-11-18.docx.
No c.3001G>A, p.Glu1001Lys, or p.E1001K entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.
PM5N/ANot applicable: ENIGMA excludes classic missense PM5 and reserves PM5 for genomic PTC variants annotated with PVS1.
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Reasoning
The variant is missense. ENIGMA explicitly does not use classic PM5 for a missense change at a residue with a different pathogenic missense change; its repurposed PM5 applies only to genomic protein-termination-codon variants annotated with PVS1. This variant is not a PTC or truncating variant.
VCEP rule
Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. ... Do not use ... Protein termination codon (PTC) variant in an exon where a different proven pathogenic PTC variant has been seen before. Use to justify additional weight for PTC variants annotated as PVS1. ... Only applied to genomic PTC changes (not splicing).
Evidence considered
Case normalization identifies c.3001G>A as a missense substitution producing p.Glu1001Lys, not a protein-termination-codon change.
Specifications v1.2 PM5 entry: classic missense PM5 is marked 'Do not use'; the repurposed PM5_VariableWeight (PTC) is only for genomic PTC changes and provides additional weight to PVS1-annotated PTC variants.
Table 4 and Supplementary Table 1 were searched for the three variant notations; no matching variant row was found.
Still missing
No matching c.3001G>A, p.Glu1001Lys, or p.E1001K entry was found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt.
No matching c.3001G>A, p.Glu1001Lys, or p.E1001K entry was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
PM6VCEPNot applicable: the ENIGMA specification explicitly says not to use PM6 because de novo occurrences lack calibrated predictive value.
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Reasoning
The ENIGMA BRCA1 Version 1.2 specification explicitly says not to use PM6 because BRCA1/2-related cancers occur relatively commonly and there is no information to calibrate the predictive capacity of de novo occurrences.
VCEP rule
Confirmed de novo without confirmation of paternity and maternity. ... Do not use ... BRCA1/2-related cancers occur relatively commonly. No information to calibrate the predictive capacity of de novo occurrences.
Evidence considered
Specifications_V1.2-2024-11-18.docx, PM6 entry: the criterion is marked "Do not use" because BRCA1/2-related cancers occur relatively commonly and de novo predictive capacity is not calibrated.
PP2VCEPNot applicable: ENIGMA says PP2 is not used because BRCA1 has a high frequency of benign missense variants.
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Reasoning
The ENIGMA BRCA1 VCEP explicitly marks PP2 as not to be used because BRCA1 has a high frequency of benign missense variants. No PP2 assessment is therefore applicable to this missense variant.
VCEP rule
Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. ... Do not use ... High frequency of benign missense variants.
Evidence considered
Specifications v1.2, Table 1 PP2 entry: PP2 is marked 'Do not use' with the reason 'High frequency of benign missense variants.'
PP5VCEPNot applicable: the ENIGMA BRCA1 VCEP explicitly prohibits use of PP5 regardless of reported pathogenic classifications.
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Reasoning
The ENIGMA BRCA1 VCEP explicitly does not use PP5. Variant-level reports in ClinVar or other reputable sources therefore cannot establish PP5 under this governing framework.
VCEP rule
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Evidence considered
ENIGMA CSPEC marks PP5 Not Applicable for this VCEP and states: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
ClinVar contains no expert-panel submission for this exact variant, but that does not change the VCEP prohibition on PP5.
BP2VCEPNot applicable: the VCEP explicitly says BP2 is not used and is applied only in the context of BS2.
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Reasoning
The ENIGMA BRCA1 VCEP explicitly marks BP2 as not to be used and limits it to the context of BS2. BP2 is therefore not applicable for this criterion assessment, regardless of whether phase or co-occurrence information is available.
VCEP rule
Do not use ... Applied only in the context of BS2.
Evidence considered
Specifications_V1.2_2024-11-18.docx.txt, Table 1 BP2 row: the criterion is marked 'Do not use' and 'Applied only in the context of BS2.'
vcep_materials.json / prefetch.json CSPEC criterion entry marks BP2 as Not Applicable and states 'Applied only in the context of BS2.'
BP3VCEPNot applicable: p.(E1001K) is missense rather than an in-frame indel in a nonfunctional repetitive region, and ENIGMA explicitly says BP3 is not to be used.
Details ▾Hide ▴
Reasoning
The variant is a missense substitution, not an in-frame deletion or insertion in a repetitive region without a known function. ENIGMA BRCA1/2 v1.2 explicitly marks BP3 as not to be used and states that this evidence is captured by bioinformatic tool prediction and domain analysis. The required VCEP files were searched for c.3001G>A, p.Glu1001Lys, and p.E1001K: no variant-level entry was found in Specifications_Table4_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.
VCEP rule
In-frame deletions/insertions in a repetitive region without a known function ... Do not use ... Captured by bioinformatic tool prediction, and domain analysis.
Evidence considered
Case variant assessment: NM_007294.4:c.3001G>A; NP_009225.1:p.(Glu1001Lys) / p.(E1001K); consequence_class = missense.
Specifications_V1.2_2024-11-18.docx, Table 1, BP3: in-frame deletions/insertions in a repetitive region without a known function; BP3 is marked 'Do not use' and captured by bioinformatic tool prediction and domain analysis.
Still missing
No c.3001G>A, p.Glu1001Lys, or p.E1001K entry was found in Specifications_Table4_V1.2_2024-11-18.xlsx.
No c.3001G>A, p.Glu1001Lys, or p.E1001K entry was found in Specifications_V1.2_2024-11-18.docx.
No c.3001G>A, p.Glu1001Lys, or p.E1001K entry was found in Appendices_V1.2_2024-11-18.docx.
No c.3001G>A, p.Glu1001Lys, or p.E1001K entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.
BP4N/ANot applicable: p.Glu1001Lys is a missense variant outside the VCEP-defined BRCA1 domains covered by the BP4 missense path.
Details ▾Hide ▴
Reasoning
The VCEP BP4 missense path is limited to missense or in-frame insertion, deletion, or delins variants inside a potentially clinically important functional domain. p.(Glu1001Lys) is outside the VCEP-defined BRCA1 RING, coiled-coil, and BRCT domains; the silent and intronic BP4 paths do not apply to this missense variant. No exact c.3001G>A, p.Glu1001Lys, or p.E1001K entry was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt, Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, or PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
VCEP rule
Missense or in-frame insertion, deletion or delins variants inside a (potentially) clinically important functional domain, and no predicted impact via protein change or splicing (BayesDel no-AF score ≤0.15 AND SpliceAI ≤0.1). ... Silent variant inside a (potentially) clinically important functional domain, if no predicted impact via splicing (SpliceAI ≤0.1). ... Intronic variants outside of the native donor and acceptor splice sites (i.e. not +/- 1,2 positions) AND no predicted impact via splicing (SpliceAI ≤0.1).
Evidence considered
The VCEP BP4 missense rule applies only inside a potentially clinically important functional domain and requires BayesDel no-impact plus SpliceAI ≤0.1.
The VCEP-defined BRCA1 clinically important domains are RING aa 2-101, coiled-coil aa 1391-1424, and BRCT repeats aa 1650-1857; p.Glu1001Lys is outside these domains.
Exact-notation searches for c.3001G>A, p.Glu1001Lys, and p.E1001K found no entry in the four governing full-text files named for this case.
Still missing
No exact c.3001G>A, p.Glu1001Lys, or p.E1001K entry found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
No exact c.3001G>A, p.Glu1001Lys, or p.E1001K entry found in Specifications_V1.2_2024-11-18.docx.txt.
No exact c.3001G>A, p.Glu1001Lys, or p.E1001K entry found in Appendices_V1.2_2024-11-18.docx.txt.
No exact c.3001G>A, p.Glu1001Lys, or p.E1001K entry found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
BP6VCEPNot applicable: the ENIGMA BRCA1 VCEP explicitly prohibits use of BP6 regardless of reported benign classifications.
Details ▾Hide ▴
Reasoning
The ENIGMA BRCA1 VCEP explicitly does not use BP6. Benign classifications in ClinVar or other reputable sources therefore cannot establish BP6 under this governing framework.
VCEP rule
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Evidence considered
ENIGMA CSPEC marks BP6 Not Applicable for this VCEP and states: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
ClinVar includes one weak single-submitter likely-benign record, but it cannot be converted into BP6 under the VCEP rule.
BP7N/ANot applicable: BP7 is restricted to silent or qualifying intronic variants, whereas p.Glu1001Lys is missense.
Details ▾Hide ▴
Reasoning
The VCEP BP7 paths cover silent variants inside a potentially clinically important functional domain or intronic variants outside conserved donor or acceptor motif positions, and do not cover missense substitutions. This variant is missense, p.(Glu1001Lys), so BP7 is not applicable regardless of its SpliceAI result. No exact c.3001G>A, p.Glu1001Lys, or p.E1001K entry was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt, Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, or PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
VCEP rule
Apply BP7 for ... Silent variant inside a (potentially) clinically important functional domain, IF BP4 met. ... Intronic variants located outside conserved donor or acceptor motif positions (at or beyond positions +7/-21) IF BP4 met
Evidence considered
The VCEP BP7 rule applies to silent variants inside a potentially clinically important functional domain or intronic variants outside conserved donor or acceptor motif positions, if BP4 is met.
The case variant is the missense substitution NM_007294.4:c.3001G>A, p.(Glu1001Lys), not a silent or intronic variant.
Exact-notation searches for c.3001G>A, p.Glu1001Lys, and p.E1001K found no entry in the four governing full-text files named for this case.
Still missing
No exact c.3001G>A, p.Glu1001Lys, or p.E1001K entry found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
No exact c.3001G>A, p.Glu1001Lys, or p.E1001K entry found in Specifications_V1.2_2024-11-18.docx.txt.
No exact c.3001G>A, p.Glu1001Lys, or p.E1001K entry found in Appendices_V1.2_2024-11-18.docx.txt.
No exact c.3001G>A, p.Glu1001Lys, or p.E1001K entry found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Every interpreted variant in BRCA1, mapped onto the exon structure of NM_007294.4. Select a row to find it on the plot.
BRCA1NM_007294.4
Fetching transcript structure from UCSC…
Exons
—
Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in BRCA1—Select a row to find it on the plot; use the link to open its page.
Protein
Location
Classification
Link
gnomAD v4.1Allele count data not recorded
gnomAD v2.1Allele count data not recorded
gnomAD-Canada v1.0Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
SpliceAI acceptor lossat +374 bp
0.000
SpliceAI acceptor gainat -391 bp
0.004
SpliceAI donor lossat -65 bp
0.001
SpliceAI donor gainat +21 bp
0.000
Pangolin splice lossmagnitude shown
-0.003
Pangolin splice gain
0.007
Other predictors
REVEL
0.417
BayesDel
-0.164
How the predictions were used
PP3VCEPNot met: SpliceAI maximum delta 0.004 is below the VCEP PP3 splice threshold of ≥0.2 for this missense variant.
Details ▾Hide ▴
Reasoning
The variant is a missense substitution, p.(Glu1001Lys), outside the VCEP-defined BRCA1 clinically important domains (RING aa 2-101, coiled-coil aa 1391-1424, BRCT repeats aa 1650-1857). Therefore the PP3 protein-impact path does not apply. The VCEP's splice-prediction path does apply to missense variants irrespective of domain location, but requires SpliceAI ≥0.2; the case SpliceAI maximum delta score is 0.004, so PP3 is not met. No exact c.3001G>A, p.Glu1001Lys, or p.E1001K entry was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt, Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, or PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
VCEP rule
Do not apply PP3 if PVS1 is met at any strength. ... Apply PP3 for missense or in-frame insertion, deletion or delins variants inside a (potentially) clinically important functional domain and predicted impact via protein change (BayesDel predicted Impact). ... Apply PP3 for predicted splicing (SpliceAI ≥0.2) for silent, missense/in-frame (irrespective of location in clinically important functional domain) and for intronic variants outside of the donor and acceptor ±1,2 positions.
Evidence considered
The VCEP CSPEC rule identifies the variant as a missense substitution and permits the splice-prediction path irrespective of functional-domain location, requiring SpliceAI ≥0.2.
SpliceAI result for NM_007294.4:c.3001G>A: DS_AG 0.004, DS_AL 0.000, DS_DG 0.000, DS_DL 0.001; maximum delta score 0.004.
The VCEP-defined clinically important BRCA1 domains are RING aa 2-101, coiled-coil aa 1391-1424, and BRCT repeats aa 1650-1857; p.Glu1001Lys is outside these domains.
Exact-notation searches for c.3001G>A, p.Glu1001Lys, and p.E1001K found no entry in the four governing full-text files named for this case.
Still missing
No exact c.3001G>A, p.Glu1001Lys, or p.E1001K entry found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
No exact c.3001G>A, p.Glu1001Lys, or p.E1001K entry found in Specifications_V1.2_2024-11-18.docx.txt.
No exact c.3001G>A, p.Glu1001Lys, or p.E1001K entry found in Appendices_V1.2_2024-11-18.docx.txt.
No exact c.3001G>A, p.Glu1001Lys, or p.E1001K entry found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
BP4N/ANot applicable: p.Glu1001Lys is a missense variant outside the VCEP-defined BRCA1 domains covered by the BP4 missense path.
Details ▾Hide ▴
Reasoning
The VCEP BP4 missense path is limited to missense or in-frame insertion, deletion, or delins variants inside a potentially clinically important functional domain. p.(Glu1001Lys) is outside the VCEP-defined BRCA1 RING, coiled-coil, and BRCT domains; the silent and intronic BP4 paths do not apply to this missense variant. No exact c.3001G>A, p.Glu1001Lys, or p.E1001K entry was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt, Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, or PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
VCEP rule
Missense or in-frame insertion, deletion or delins variants inside a (potentially) clinically important functional domain, and no predicted impact via protein change or splicing (BayesDel no-AF score ≤0.15 AND SpliceAI ≤0.1). ... Silent variant inside a (potentially) clinically important functional domain, if no predicted impact via splicing (SpliceAI ≤0.1). ... Intronic variants outside of the native donor and acceptor splice sites (i.e. not +/- 1,2 positions) AND no predicted impact via splicing (SpliceAI ≤0.1).
Evidence considered
The VCEP BP4 missense rule applies only inside a potentially clinically important functional domain and requires BayesDel no-impact plus SpliceAI ≤0.1.
The VCEP-defined BRCA1 clinically important domains are RING aa 2-101, coiled-coil aa 1391-1424, and BRCT repeats aa 1650-1857; p.Glu1001Lys is outside these domains.
Exact-notation searches for c.3001G>A, p.Glu1001Lys, and p.E1001K found no entry in the four governing full-text files named for this case.
Still missing
No exact c.3001G>A, p.Glu1001Lys, or p.E1001K entry found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
No exact c.3001G>A, p.Glu1001Lys, or p.E1001K entry found in Specifications_V1.2_2024-11-18.docx.txt.
No exact c.3001G>A, p.Glu1001Lys, or p.E1001K entry found in Appendices_V1.2_2024-11-18.docx.txt.
No exact c.3001G>A, p.Glu1001Lys, or p.E1001K entry found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
BP7N/ANot applicable: BP7 is restricted to silent or qualifying intronic variants, whereas p.Glu1001Lys is missense.
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Reasoning
The VCEP BP7 paths cover silent variants inside a potentially clinically important functional domain or intronic variants outside conserved donor or acceptor motif positions, and do not cover missense substitutions. This variant is missense, p.(Glu1001Lys), so BP7 is not applicable regardless of its SpliceAI result. No exact c.3001G>A, p.Glu1001Lys, or p.E1001K entry was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt, Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, or PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
VCEP rule
Apply BP7 for ... Silent variant inside a (potentially) clinically important functional domain, IF BP4 met. ... Intronic variants located outside conserved donor or acceptor motif positions (at or beyond positions +7/-21) IF BP4 met
Evidence considered
The VCEP BP7 rule applies to silent variants inside a potentially clinically important functional domain or intronic variants outside conserved donor or acceptor motif positions, if BP4 is met.
The case variant is the missense substitution NM_007294.4:c.3001G>A, p.(Glu1001Lys), not a silent or intronic variant.
Exact-notation searches for c.3001G>A, p.Glu1001Lys, and p.E1001K found no entry in the four governing full-text files named for this case.
Still missing
No exact c.3001G>A, p.Glu1001Lys, or p.E1001K entry found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
No exact c.3001G>A, p.Glu1001Lys, or p.E1001K entry found in Specifications_V1.2_2024-11-18.docx.txt.
No exact c.3001G>A, p.Glu1001Lys, or p.E1001K entry found in Appendices_V1.2_2024-11-18.docx.txt.
No exact c.3001G>A, p.Glu1001Lys, or p.E1001K entry found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.417. BayesDel score = -0.163974.
6 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
Systematic misclassification of missense variants in BRCA1 and BRCA2 "coldspots".
Dines JN et al. · 2020
The paper does not explicitly mention BRCA1 c.3001G>A or p.(E1001K). It analyzed curated ClinVar missense variants by BRCA1 region and reported exon 11 as a broad missense coldspot, with no confirmed pathogenic or likely pathogenic missense variants in that exon, but it did not provide a variant-specific functional assay result for this variant.
By contrast, exon 11 accounts for ~60% of the coding sequence but has no confirmed P\u2009+\u2009LP missense variants, and 58.0% (69/119) of B\u2009+\u2009LB variants.
American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography.
Saslow D et al. · 2007
The paper does not mention this variant and discusses BRCA1 mutation carriers only in the context of breast MRI screening and general hereditary cancer risk.
Two breast/ovarian cancer susceptibility genes, BRCA1 and BRCA2, have been identified.
Genetic Testing section; Table 1
NSGC practice guideline: risk assessment and genetic counseling for hereditary breast and ovarian cancer.
The paper does not explicitly mention BRCA1 c.3001G>A or NP_009225.1:p.(E1001K); it provides general BRCA1 hereditary cancer context and states that VUS results should not be used as disease classification.
BRCA1 and BRCA2 are tumor suppressor genes. Their protein products are involved in the cellular response to DNA damage and double-stranded DNA repair.
Clinical Features; Recommendation 4
Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women: U.S. Preventive Services Task Force recommendation statement.
The paper does not mention this variant and reports only general hereditary BRCA1/2 cancer-risk context, without variant-specific case-control or clinical LR evidence.
For example, in the short term, BRCA1/BRCA2-positive genetic test results can affect surgical decisions and may soon have an impact on systemic treatment options.
Introduction
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The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories). (ClinVarID = 822554)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.417. BayesDel score = -0.163974.
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 not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
This variant was interpreted by pipeline 11.0.02.
The current version is 11.0.07.
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