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BRCA1c.4481A>GUncertain significance
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Variant interpretation report

BRCA1 c.4481A>G, p.(Glu1494Gly)

NM_007294.4:c.4481A>G NP_009225.1:p.(Glu1494Gly) Missense · exon 13 View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

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.

NCBI Gene ↗ OncoKB ↗
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.

Pathogenic evidence criteria: 0 Benign evidence criteria: 0
Pathogenic criteria applied · 0

No pathogenic criterion marked as applied in the recorded assessment.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

VUS: no adjudicated criterion was met or assigned a usable strength under the ENIGMA BRCA1 VCEP Version 1.2 Table 3 framework.

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
5 / 1,613,712 alleles

gnomAD v4.1: 5 / 1,613,712 alleles. Recorded AF 3.09845e-06. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 3.98057e-06; MAF= 0.00040%, 1/251220 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 3.26669e-05; MAF= 0.00327%, 1/30612 alleles, homozygotes = 0).

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

No listed criterion applied
gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗
No screenshot for this evidence
REVEL score
0.492 recorded score

Recorded REVEL score: 0.492. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied
ClinVar submissions
5 reported laboratory submissions

4 Uncertain significance · 1 Uncertain Significance. ClinVar API review status: criteria provided, multiple submitters, no conflicts.

Context only ClinVar ↗
Functional evidence
Statement recorded

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.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under ClinGen BRCA1 VCEP v1.2, with the data and sources behind each one.

28 criteria with recorded statuses: 0 met · 4 not met · 9 not assessed · 15 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

All three requested criteria are not applicable under the ENIGMA BRCA1/2 VCEP v1.2 rules: PVS1 is limited to null variants, while PM4 and BP3 are explicitly marked Do not use.

The queried variant is NM_007294.4:c.4481A>G, encoding NP_009225.1:p.(Glu1494Gly), and is not a canonical splice-site, in-frame length-change, or repeat-region in-frame variant.

For this codon/residue/domain group, PS1 and BP1 are not met because no qualifying pathogenic same-amino-acid comparator was found and SpliceAI max delta 0.122 exceeds the VCEP's 0.1 no-splicing requirement; PM1, PM5, and PP2 are explicitly not used by ENIGMA for this missense variant or framework.

The variant is missense (NM_007294.4:c.4481A>G; NP_009225.1:p.(Glu1494Gly), p.E1494G).

PP3 is in scope through the VCEP's missense splicing path but is not met because SpliceAI max delta 0.122 is below ≥0.2; the protein-impact path is outside scope because residue 1494 is outside the defined functional domains.

BP4 is not applicable because its missense path is restricted to variants inside a defined functional domain.

BP7 is not applicable because the variant is missense rather than silent or intronic.

Not met · 4 · evaluated, threshold not reached

PS1 VCEPNot met: no pathogenic same-amino-acid comparator was found, and the same-residue c.4480G>A comparator is BS3 Strong rather than pathogenic. Details ▾Hide ▴
Reasoning

The variant is a missense substitution, and SpliceAI max delta is 0.122, exceeding the VCEP's no-splicing threshold of 0.1. The governing ENIGMA files contain no pathogenic or likely pathogenic BRCA1 variant producing the same p.Glu1494Gly substitution. The only same-residue comparator identified is c.4480G>A (p.Glu1494Lys), which is assigned BS3 Strong/No functional impact rather than pathogenic or likely pathogenic evidence. 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)).
Evidence considered
  • ENIGMA Specifications v1.2, PS1 rule: a missense PS1 call requires a previously classified pathogenic variant acting via protein change with no confirmed or predicted mRNA-splicing effect (SpliceAI <=0.1); the case variant has SpliceAI max delta 0.122.
  • ENIGMA Specifications Table 9, BRCA1 c.4480G>A (p.Glu1494Lys): BS3 Strong; reported protein function similar to benign controls; Fernandes 2019 (PMID:30765603) - Not Pathogenic.
  • ENIGMA Supplementary Tables, ST4 row 1026, BRCA1 c.4480G>A (p.Glu1494Lys): No functional impact; IARC class 1, Not Pathogenic.
  • The three requested variant notations were searched across the named governing full-text files; c.4481A>G occurred only in the separate Li et al. clinical-history LR file, not as a same-amino-acid pathogenic comparator.
Still missing
  • No pathogenic or likely pathogenic same-amino-acid comparator was found in Specifications_V1.2_2024-11-18.docx, Appendices_V1.2_2024-11-18.docx, SupplementaryTables_V1.2_2024-11-18.xlsx, Specifications_Table4_V1.2_2024-11-18.xlsx, or Specifications_Table9_V1.2_2024-11-18.xlsx when searched for c.4481A>G, p.Glu1494Gly, and p.E1494G.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_specifications_table9_v1_2_2024_11_18 ↗vcep_supplementarytables_v1_2_2024_11_18 ↗
PM2 VCEPNot met: the variant was present in gnomAD v2.1 non-cancer exomes at AF 4.22494e-06, so it was not absent from controls. Details ▾Hide ▴
Reasoning

The ENIGMA PM2 rule requires absence from controls in an outbred population in gnomAD v2.1 non-cancer exomes and gnomAD v3.1 non-cancer, with average read depth at least 25. The variant is present in gnomAD v2.1 non-cancer exomes at AF 4.22494e-06 (1/236690 alleles; 0 homozygotes), so the required absence condition is not satisfied. It is also reported absent from gnomAD v3.1 non-cancer, but that does not overcome presence in the required v2.1 non-cancer source.

VCEP rule
Absent from controls in an outbred population, from gnomAD v2.1 (non-cancer, exome only subset) and gnomAD v3.1 (non-cancer). Region around the variant must have an average read depth ≥25. See Appendix G for details.
Evidence considered
  • The governing CSPEC rule requires the variant to be absent from controls in gnomAD v2.1 non-cancer exome-only data and gnomAD v3.1 non-cancer data, with average read depth >=25.
  • GNOMAD_V2_1_NON_CANCER: variant present in non-cancer exomes with AF 4.22494e-06, 1/236690 alleles, and 0 homozygotes.
  • GNOMAD_V3_1_NON_CANCER: variant reported absent.
Sources
cspec ↗vcep_appendices_v1_2_2024_11_18 ↗gnomad_v2 ↗
PP3 VCEPNot met: SpliceAI max delta 0.122 is below the ENIGMA PP3 splicing threshold of ≥0.2 for missense variants. Details ▾Hide ▴
Reasoning

The variant is a missense substitution at p.Glu1494Gly (p.E1494G), so the VCEP's missense splicing path is applicable irrespective of functional-domain location. The governing rule requires SpliceAI ≥0.2 for PP3 on this path. The case evidence reports SpliceAI max delta 0.122 (DS_AL 0.122), below the threshold, so PP3 is not met. The BayesDel no-AF score is -0.107518, and residue 1494 is outside the VCEP-defined coiled-coil domain (aa 1391-1424) and BRCT domain (aa 1650-1857); therefore no protein-impact PP3 path applies. No variant-level 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 for c.4481A>G, p.Glu1494Gly, or p.E1494G.

VCEP rule
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
  • ENIGMA BRCA1 specification v1.2, PP3 rule: predicted splicing uses SpliceAI ≥0.2 for silent and missense/in-frame variants irrespective of location in a clinically important functional domain.
  • SpliceAI Lookup for NM_007294.4:c.4481A>G: DS_AG=0.001, DS_AL=0.122, DS_DG=0.000, DS_DL=0.088; maximum delta score=0.122.
  • ENIGMA BRCA1 specification v1.2, Appendix J: protein-impact PP3 for BRCA1 requires BayesDel no-AF ≥0.28 inside a defined clinically important functional domain; the observed score is -0.107518 and p.Glu1494 is outside the defined domains.
  • Variant search result: no matching entry for c.4481A>G, p.Glu1494Gly, or p.E1494G in the four governing full-text files named in gaps_remaining.
Still missing
  • No variant-level entry found for c.4481A>G, p.Glu1494Gly, or p.E1494G in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No variant-level entry found for c.4481A>G, p.Glu1494Gly, or p.E1494G in Specifications_V1.2_2024-11-18.docx.txt.
  • No variant-level entry found for c.4481A>G, p.Glu1494Gly, or p.E1494G in Appendices_V1.2_2024-11-18.docx.txt.
  • No variant-level entry found for c.4481A>G, p.Glu1494Gly, or p.E1494G in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗spliceai ↗bayesdel
BP1 VCEPNot met: residue 1494 is outside approved domains, but SpliceAI max delta 0.122 exceeds the BP1_Strong threshold of <=0.1. Details ▾Hide ▴
Reasoning

The variant is missense and residue 1494 is outside the VCEP-defined BRCA1 clinically important domains, satisfying the location component of BP1_Strong. However, the VCEP requires no predicted splicing with SpliceAI <=0.1, while the case's maximum SpliceAI delta is 0.122. Therefore BP1_Strong is not met.

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
  • ENIGMA Specifications v1.2, BP1_Strong: applies to missense variants outside a potentially clinically important functional domain and requires no splicing predicted (SpliceAI <=0.1); missense prediction is not applicable.
  • Case SpliceAI result: max delta score 0.122 (DS_AL 0.001, DS_AL 0.122, DS_DL 0.088), which exceeds the VCEP BP1 no-splicing threshold.
  • ENIGMA domain definitions place the BRCA1 coiled-coil at aa 1391-1424, RING at aa 2-101, and BRCT repeats at aa 1650-1857; residue 1494 is outside all three.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗

Not assessed · 9 · no assessment recorded

PS3 VCEPNot assessed: ENIGMA Table 9 and ST4 contain no c.4481A>G functional-assay entry or calibrated damaging-effect assignment. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1 VCEP reserves PS3 for well-established in vitro or in vivo functional studies supportive of a damaging effect measured through protein alone or combined mRNA and protein, with calibrated code recommendations in Specifications Table 9. The required variant searches found no entry for c.4481A>G, p.Glu1494Gly, or p.E1494G in Specifications_Table9_V1.2_2024-11-18.xlsx.txt or SupplementaryTables_V1.2_2024-11-18.xlsx.txt ST4. The available case literature extracts do not contain variant-specific functional assay evidence. Therefore, PS3 cannot be assigned from the available VCEP-governed evidence.

VCEP rule
Well-established in vitro or in vivo functional studies supportive of a damaging effect. Apply PS3 for assays measuring effect via protein only OR mRNA and protein combined. See Specifications Table 9 for code recommendations from calibrated published assays. Also see Figure1C and Appendix E for details.
Evidence considered
  • ENIGMA BRCA1 Specifications Table 9: searched c.4481A>G, p.Glu1494Gly, and p.E1494G; no matching variant row was found. The nearby c.4480G>A p.(Glu1494Lys) row is a different variant and was not transferred.
  • ENIGMA BRCA1 Supplementary Table ST4: searched c.4481A>G, p.Glu1494Gly, and p.E1494G in the full functional assay results dataset; no matching variant row was found.
  • ENIGMA BRCA1 Appendix E and Specifications v1.2: PS3 is reserved for well-established functional studies showing a damaging effect through protein alone or combined mRNA and protein, with calibrated recommendations from Table 9.
Still missing
  • No entry for c.4481A>G, p.Glu1494Gly, or p.E1494G was found in Specifications_Table9_V1.2_2024-11-18.xlsx.txt.
  • No entry for c.4481A>G, p.Glu1494Gly, or p.E1494G was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt ST4.
  • No variant-specific functional assay publication was available in the case literature extracts.
Sources
cspec ↗vcep_specifications_table9_v1_2_2024_11_18 ↗vcep_supplementarytables_v1_2_2024_11_18 ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗
PS4 VCEPNot assessed: no variant-specific case-control p-value, odds ratio, or confidence interval is available to test the PS4 requirements. Details ▾Hide ▴
Reasoning

The governing VCEP rule requires a case-control study with p-value ≤0.05 and OR ≥4, with the lower confidence interval excluding 2.0. No variant-specific case-control counts, odds ratio, p-value, or confidence interval were available. The VCEP also states that proband counting is not to be used as originally described, so the available clinical-history record cannot substitute for PS4.

VCEP rule
The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls. ... Case-control studies; p-value ≤0.05 and OR ≥4 (lower confidence interval excludes 2.0). ... If case-control LR estimates are available for a given dataset, these should be used in preference to case-control OR data, under code PP4 (or BP5, if appropriate). ... Proband Counting: prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls ... Do not use Proband Counting as originally described.
Evidence considered
  • No case-control enrichment dataset for BRCA1 c.4481A>G / p.Glu1494Gly was identified in the case evidence.
  • The Li et al. clinical-history table is a multifactorial clinical-history LR component and is not case-control evidence for PS4.
Still missing
  • No variant-specific case-control study data with p-value, OR, and lower confidence interval were available.
Sources
cspec ↗
PM3 VCEPNot assessed: no documented same-gene pathogenic/likely pathogenic co-occurrence, phase, or BRCA1-related Fanconi Anemia phenotype was available to assign the VCEP's 1-, 2-, or ≥4-point PM3 threshold. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1 VCEP limits PM3 to a patient with a phenotype consistent with BRCA1-related Fanconi Anemia and a co-occurrent pathogenic or likely pathogenic variant in the same gene. The case-evidence bundle does not document a same-gene pathogenic/likely pathogenic co-occurrence, phase or homozygosity, chromosome-breakage testing, or the VCEP-defined Fanconi Anemia clinical features needed to assign PM3-related points. The governing Table 6 assigns 2 points for a pathogenic/likely pathogenic variant in trans or a homozygote and 1 point when phase is unknown, with final PM3 strength requiring 1, 2, or at least 4 total points; no point can be assigned from the available evidence.

VCEP rule
For recessive disorders, detected in trans with a pathogenic variant. ... 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.
Evidence considered
  • Specifications_V1.2_2024-11-18.docx, Table 1 PM3 rule: PM3 applies for a patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia and co-occurrent variants in the same gene; the specified phenotype requires increased chromosome breakage plus one clinical feature, or at least two clinical features from at least two categories when breakage is unknown.
  • Specifications_V1.2_2024-11-18.docx, Table 6: a pathogenic or likely pathogenic variant in trans or homozygote contributes 2 points, while phase unknown contributes 1 point; final PM3 assignment is PM3_Supporting at 1 point, PM3 at 2 points, and PM3_Strong at 4 or more points.
  • The case-evidence bundle was searched for phase, in-trans, in-cis, co-occurrence, Fanconi Anemia, chromosome-breakage, and proband evidence; no case-specific allelic observation satisfying the PM3 prerequisites was found.
  • The governing VCEP full-text file was searched for c.4481A>G, p.Glu1494Gly, and p.E1494G; c.4481A>G was found only in PMID_31853058_BRCA1_clinical_history_LR.xlsx as a clinical-history LR row, with no PM3 allelic observation, and the protein notations had no matches.
Still missing
  • No same-gene pathogenic or likely pathogenic co-occurring variant is documented for NM_007294.4:c.4481A>G in the case-evidence bundle.
  • No phase determination, homozygous observation, or parent/offspring genotyping is documented.
  • No chromosome-breakage result or VCEP-defined BRCA1-related Fanconi Anemia physical, pathology/laboratory, or cancer diagnosis ≤5 years evidence is documented.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗
PP1 VCEPNot assessed: no quantitative affected-family co-segregation data or Bayes-score likelihood ratio was available to compare with the PP1 threshold of LR ≥2.08:1. Details ▾Hide ▴
Reasoning

No quantitative co-segregation analysis, affected-family-member genotype data, meioses, or Bayes-score likelihood ratio for NM_007294.4:c.4481A>G was provided. The VCEP requires co-segregation in multiple affected family members measured by a quantitative method and assigns PP1 strength from the resulting LR; therefore PP1 cannot be assessed. The exact variant was not found in Specifications_V1.2_2024-11-18.docx.txt or HUMU-40-1557-s001.xlsx.txt.

VCEP rule
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease, as measured by a quantitative co-segregation analysis method. ... 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: requires co-segregation with disease in multiple affected family members measured by a quantitative co-segregation method; PP1 Supporting requires LR ≥2.08:1, PP1 Moderate LR ≥4.3:1, PP1 Strong LR ≥18.7:1, and PP1 Very Strong LR ≥350:1.
  • The case evidence bundle contains no quantitative segregation result, affected-relative genotype table, meiosis count, or PP1 Bayes-score LR for this variant.
  • HUMU-40-1557-s001.xlsx was searched under c.4481A>G, p.Glu1494Gly, and p.E1494G; no matching entry was found. Its index guidance also limits the file to multifactorial likelihood data and does not authorize using its clinical-history data alone for PP1.
  • Specifications_V1.2_2024-11-18.docx.txt was searched under c.4481A>G, p.Glu1494Gly, and p.E1494G; no matching variant entry was found.
Still missing
  • No quantitative co-segregation analysis, affected-relative genotypes, meioses, or Bayes-score LR for NM_007294.4:c.4481A>G was provided.
  • No entry for c.4481A>G, p.Glu1494Gly, or p.E1494G was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No entry for c.4481A>G, p.Glu1494Gly, or p.E1494G was found in HUMU-40-1557-s001.xlsx.txt.
Sources
cspec ↗
BA1 VCEPNot assessed: gnomAD v2.1 non-cancer AF was 4.22494e-06, but the VCEP requires FAF >0.001 and FAF was unavailable. Details ▾Hide ▴
Reasoning

The governing ENIGMA rule requires filter allele frequency (FAF) above 0.1% in the specified non-cancer, non-founder gnomAD populations. The available gnomAD v2.1 non-cancer exome record reports allele frequency 4.22494e-06 (1/236690 alleles; 0 homozygotes), and gnomAD v3.1 non-cancer is reported absent, but the required FAF value is null/not available. Therefore the FAF threshold cannot be evaluated without substituting AF for FAF, which the VCEP rule does not permit.

VCEP rule
Filter allele frequency (FAF) is above 0.1% (FAF > 0.001) in gnomAD v2.1 (non-cancer, exome only subset) and/or gnomAD v3.1 (non-cancer), non-founder population(s). See Appendix G for details.
Evidence considered
  • The governing CSPEC rule specifies: Filter allele frequency (FAF) is above 0.1% (FAF > 0.001) in gnomAD v2.1 (non-cancer, exome only subset) and/or gnomAD v3.1 (non-cancer), non-founder population(s).
  • Appendix G states that BA1 and BS1 should use the highest filter allele frequency in a non-founder population from gnomAD, assessing exome and genome data separately.
  • GNOMAD_V2_1_NON_CANCER: variant present in non-cancer exomes with AF 4.22494e-06, 1/236690 alleles, and 0 homozygotes; exome_grpmax_faf is null.
  • GNOMAD_V3_1_NON_CANCER: variant reported absent; no FAF value supplied.
Still missing
  • The gnomAD v2.1 non-cancer exome record has no filter allele frequency (FAF) value.
  • The gnomAD v3.1 non-cancer record is absent, but no FAF value is available for that source either.
Sources
cspec ↗vcep_appendices_v1_2_2024_11_18 ↗gnomad_v2 ↗
BS1 VCEPNot assessed: gnomAD v2.1 non-cancer AF was 4.22494e-06, but BS1 requires FAF thresholds and FAF was unavailable. Details ▾Hide ▴
Reasoning

The governing ENIGMA rule requires FAF above 0.01% for BS1 Strong or above 0.002% and at most 0.01% for BS1 Supporting, using the specified non-cancer, non-founder gnomAD populations. The available gnomAD v2.1 non-cancer record reports AF 4.22494e-06 but no FAF, and gnomAD v3.1 non-cancer is reported absent. Because FAF is the required metric, neither BS1 strength can be assigned.

VCEP rule
Filter allele frequency (FAF) is above 0.01% (FAF > 0.0001) in gnomAD v2.1 (non-cancer, exome only subset) and/or gnomAD v3.1 (non-cancer), non-founder population(s). See Appendix G for details. ... Filter allele frequency (FAF) is above 0.002% (FAF > 0.00002) and less than or equal to 0.01% (FAF ≤ 0.0001) in gnomAD v2.1 (non-cancer, exome only subset) and/or gnomAD v3.1 (non-cancer), non-founder population(s). See Appendix G for details.
Evidence considered
  • The governing CSPEC rule specifies BS1 Strong when FAF >0.0001 and BS1 Supporting when FAF >0.00002 and FAF <=0.0001 in the specified non-cancer, non-founder gnomAD populations.
  • Appendix G reports the same BS1 thresholds and requires conservative use of the highest filter allele frequency, not minor allele frequency.
  • GNOMAD_V2_1_NON_CANCER: variant present in non-cancer exomes with AF 4.22494e-06, 1/236690 alleles, and 0 homozygotes; exome_grpmax_faf is null.
  • GNOMAD_V3_1_NON_CANCER: variant reported absent; no FAF value supplied.
Still missing
  • The gnomAD v2.1 non-cancer exome record has no filter allele frequency (FAF) value.
  • The gnomAD v3.1 non-cancer record is absent, with no FAF value supplied.
Sources
cspec ↗vcep_appendices_v1_2_2024_11_18 ↗gnomad_v2 ↗
BS2 VCEPNot assessed: no qualifying trans co-occurrence, homozygote, or age/follow-up observation was available for the BS2 point system. Details ▾Hide ▴
Reasoning

The ENIGMA BS2 rule requires observations of the variant in trans with a pathogenic or likely pathogenic variant in the same gene, or as a homozygote, in presumed Fanconi-Anemia-unaffected patients, with points assigned by age or cancer follow-up and summed across observations. The case evidence contains no qualifying trans co-occurrence, homozygote, age, or follow-up observation. The zero homozygotes in gnomAD cannot supply BS2 because the VCEP specifically excludes frequency-code data from the homozygote BS2 route.

VCEP rule
Applied in absence of features of recessive disease, namely Fanconi Anemia phenotype. See **Specifications Table 8** for additional stipulations, and approach to assign points per proband, and final BS2 code assignment based on the sum of BS2-related points. See Appendix H for additional details. ... BS2 = ≥ 4 points
Evidence considered
  • The governing CSPEC rule states that BS2 is applied in the absence of Fanconi Anemia features and assigns Strong, Moderate, or Supporting strength from at least 4, 2, or 1 BS2-related points, respectively.
  • Appendix H states that BS2 points require the variant in trans with a pathogenic or likely pathogenic variant in the same gene, or as a homozygote, in a presumed Fanconi-Anemia-unaffected patient; points depend on cancer onset or unaffected follow-up at age ranges and are summed across observations.
  • Appendix H Table 13 explicitly states that homozygote BS2 application is only for phenotyped clinical or research cohorts and is not to be applied to data used for frequency-based codes.
  • GNOMAD_V2_1_NON_CANCER reports 0 homozygotes; this is frequency data and does not constitute a qualifying BS2 observation.
Still missing
  • No phenotyped patient observation in trans with a BRCA1 pathogenic or likely pathogenic variant was identified.
  • No qualifying homozygous patient observation with the required phenotype and clinical follow-up was identified.
  • No age at first cancer or last follow-up meeting the Table 13 criteria was available.
Sources
cspec ↗vcep_appendices_v1_2_2024_11_18 ↗gnomad_v2 ↗
BS3 VCEPNot assessed: ENIGMA Table 9 and ST4 contain no c.4481A>G functional-assay entry or calibrated no-damaging-effect assignment. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1 VCEP reserves BS3 for well-established in vitro or in vivo functional studies showing no damaging effect on protein function, measured through protein alone or combined mRNA and protein, with calibrated code recommendations in Specifications Table 9. The required variant searches found no entry for c.4481A>G, p.Glu1494Gly, or p.E1494G in Specifications_Table9_V1.2_2024-11-18.xlsx.txt or SupplementaryTables_V1.2_2024-11-18.xlsx.txt ST4. The available case literature extracts do not contain variant-specific functional assay evidence. Therefore, BS3 cannot be assigned from the available VCEP-governed evidence.

VCEP rule
Well-established in vitro or in vivo functional studies shows no damaging effect on protein function. Assay measures effect via protein only OR mRNA and protein combined. See Specifications Table 9 for code recommendations from calibrated published assays. Also see Figure1C and Appendix E for details.
Evidence considered
  • ENIGMA BRCA1 Specifications Table 9: searched c.4481A>G, p.Glu1494Gly, and p.E1494G; no matching variant row was found. The nearby c.4480G>A p.(Glu1494Lys) row is a different variant and was not transferred.
  • ENIGMA BRCA1 Supplementary Table ST4: searched c.4481A>G, p.Glu1494Gly, and p.E1494G in the full functional assay results dataset; no matching variant row was found.
  • ENIGMA BRCA1 Appendix E and Specifications v1.2: BS3 requires well-established functional studies showing no damaging effect on protein function, with calibrated recommendations from Table 9; mRNA-only evidence is directed to BP7 instead.
Still missing
  • No entry for c.4481A>G, p.Glu1494Gly, or p.E1494G was found in Specifications_Table9_V1.2_2024-11-18.xlsx.txt.
  • No entry for c.4481A>G, p.Glu1494Gly, or p.E1494G was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt ST4.
  • No variant-specific functional assay publication was available in the case literature extracts.
Sources
cspec ↗vcep_specifications_table9_v1_2_2024_11_18 ↗vcep_supplementarytables_v1_2_2024_11_18 ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗
BS4 VCEPNot assessed: no quantitative non-segregation data or Bayes-score likelihood ratio was available to compare with the BS4 supporting threshold of LR ≤0.48:1. Details ▾Hide ▴
Reasoning

No quantitative non-segregation analysis, affected-family-member genotype data, meioses, or Bayes-score likelihood ratio for NM_007294.4:c.4481A>G was provided. The VCEP requires lack of segregation in affected family members measured by a quantitative co-segregation method and assigns BS4 strength from the resulting LR; therefore BS4 cannot be assessed. The exact variant was not found in Specifications_V1.2_2024-11-18.docx.txt or HUMU-40-1557-s001.xlsx.txt.

VCEP rule
Lack of segregation in affected members of a family, as measured by a quantitative co-segregation analysis method. ... 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: requires lack of segregation in affected family members measured by a quantitative co-segregation method; BS4 Supporting requires LR ≤0.48:1, BS4 Moderate LR ≤0.23:1, BS4 Strong LR ≤0.05:1, and BS4 Very Strong LR ≤0.00285:1.
  • The case evidence bundle contains no quantitative non-segregation result, affected-relative genotype table, meiosis count, or BS4 Bayes-score LR for this variant.
  • HUMU-40-1557-s001.xlsx was searched under c.4481A>G, p.Glu1494Gly, and p.E1494G; no matching entry was found. Its index guidance also limits the file to multifactorial likelihood data and does not authorize using its clinical-history data alone for BS4.
  • Specifications_V1.2_2024-11-18.docx.txt was searched under c.4481A>G, p.Glu1494Gly, and p.E1494G; no matching variant entry was found.
Still missing
  • No quantitative non-segregation analysis, affected-relative genotypes, meioses, or Bayes-score LR for NM_007294.4:c.4481A>G was provided.
  • No entry for c.4481A>G, p.Glu1494Gly, or p.E1494G was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No entry for c.4481A>G, p.Glu1494Gly, or p.E1494G was found in HUMU-40-1557-s001.xlsx.txt.
Sources
cspec ↗
Not applicable · 15· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANot applicable: c.4481A>G produces p.Glu1494Gly, a missense change rather than the null-variant class required by the ENIGMA PVS1 rule. Details ▾Hide ▴
Reasoning

PVS1 is not applicable because NM_007294.4:c.4481A>G is a missense variant, NP_009225.1:p.(Glu1494Gly), whereas the ENIGMA rule is limited to null variants. The case assessment identifies the consequence as missense and not a canonical splice-site variant. Specifications_Table4_V1.2_2024-11-18.xlsx was searched for c.4481A>G, p.Glu1494Gly, and p.E1494G; no entry for this variant was found, as expected for this missense consequence.

VCEP rule
Null variant in a gene where loss of function is a known mechanism of disease.
Evidence considered
  • Case normalization: NM_007294.4:c.4481A>G; NP_009225.1:p.(Glu1494Gly) / p.(E1494G).
  • The case consequence assessment identifies this as missense and canonical_splice_consensus=false.
  • Specifications_Table4_V1.2_2024-11-18.xlsx searched for c.4481A>G, p.Glu1494Gly, and p.E1494G: no matching variant entry found.
Still missing
  • No matching c.4481A>G, p.Glu1494Gly, or p.E1494G entry was found in Specifications_Table4_V1.2_2024-11-18.xlsx.
  • No matching c.4481A>G, p.Glu1494Gly, or p.E1494G entry was found in Specifications_V1.2_2024-11-18.docx.
  • No matching c.4481A>G, p.Glu1494Gly, or p.E1494G entry was found in Appendices_V1.2_2024-11-18.docx.
  • No matching c.4481A>G, p.Glu1494Gly, or p.E1494G entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_specifications_table4_v1_2_2024_11_18 ↗
PS2 VCEPNot applicable: the ENIGMA BRCA1 VCEP explicitly says not to use PS2 because de novo occurrence lacks calibrated predictive value for these relatively common cancers. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1 VCEP specifies PS2 as de novo occurrence with confirmed paternity in an affected patient without family history, but explicitly states "Do not use" because BRCA1/2-related cancers occur relatively commonly and the predictive capacity of de novo occurrences has not been calibrated.

VCEP rule
De novo (paternity confirmed) in a patient with the disease and no family history. ... Do not use
Evidence considered
  • Specifications_V1.2_2024-11-18.docx, PS2: de novo with confirmed paternity is listed, followed by "Do not use" and the VCEP calibration rationale.
Sources
cspec ↗
PM1 VCEPNot applicable: ENIGMA says PM1 is not used, and residue 1494 lies outside the listed RING, coiled-coil, and BRCT domains. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1 specification explicitly states that PM1 is not to be used and is considered as a component of bioinformatic analysis under PP3/BP4. Independently, residue 1494 is outside the VCEP-defined BRCA1 coiled-coil domain (1391-1424), BRCT repeats (1650-1857), and RING domain (2-101), and no approved critical-domain entry includes this residue.

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
  • ENIGMA Specifications v1.2, PM1 entry: 'Do not use'; PM1 is considered as a component of bioinformatic analysis (PP3/BP4).
  • ENIGMA Specifications v1.2, domain definition: BRCA1 RING aa 2-101, coiled-coil aa 1391-1424, and BRCT repeats aa 1650-1857.
  • ENIGMA Appendices, Table 3: BRCA1 coiled-coil spans aa 1391-1424 and BRCT domains span aa 1650-1863, with the clinically important BRCT region summarized as aa 1650-1857; p.Glu1494 is outside both, and outside RING aa 2-101.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗
PM4 VCEPNot applicable: the VCEP says Do not use PM4, and c.4481A>G is a missense substitution rather than an in-frame length change or stop-loss variant. Details ▾Hide ▴
Reasoning

PM4 is explicitly designated Do not use by the ENIGMA BRCA1/2 specification. The rule describes protein-length changes from in-frame deletions/insertions in non-repeat regions or stop-loss variants, but the VCEP directs that this evidence is considered within PP3/BP4 instead; this variant is missense and does not meet the listed PM4 variant types.

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
  • Specifications_V1.2_2024-11-18.docx, Table 1 PM4 row: PM4 is marked Do not use and considered as a component of PP3/BP4.
  • Case normalization and consequence: NM_007294.4:c.4481A>G, NP_009225.1:p.(Glu1494Gly), missense.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗
PM5 N/ANot applicable: ENIGMA does not use missense PM5, and this p.Glu1494Gly missense variant is not a PVS1 protein-termination-codon variant. Details ▾Hide ▴
Reasoning

The variant is missense. ENIGMA explicitly marks the original missense PM5 criterion 'Do not use' and reserves the repurposed PM5 variable-weight code for protein-termination-codon variants annotated PVS1. This variant is not a PTC and is not eligible for PM5_PTC.

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 Considered as component of bioinformatic analysis (PP3/BP4).
Evidence considered
  • ENIGMA Specifications v1.2, original PM5 entry: missense change at an amino acid residue with a different pathogenic missense change; 'Do not use'; considered as a component of PP3/BP4.
  • ENIGMA Specifications v1.2, PM5_VariableWeight (PTC): applies to a protein termination codon variant in an exon with a different proven pathogenic PTC variant and is used for PTC variants annotated PVS1.
  • Case variant facts: NM_007294.4:c.4481A>G, p.(Glu1494Gly), consequence class missense; therefore the Table 4 PM5_PTC exon lookup is outside the named variant type.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_specifications_table4_v1_2_2024_11_18 ↗vcep_supplementarytables_v1_2_2024_11_18 ↗
PM6 VCEPNot applicable: the ENIGMA BRCA1 VCEP explicitly says not to use PM6 because de novo occurrence lacks calibrated predictive value for these relatively common cancers. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1 VCEP specifies PM6 as confirmed de novo occurrence without confirmation of paternity and maternity, but explicitly states "Do not use" because BRCA1/2-related cancers occur relatively commonly and the predictive capacity of de novo occurrences has not been calibrated.

VCEP rule
Confirmed de novo without confirmation of paternity and maternity. ... Do not use
Evidence considered
  • Specifications_V1.2_2024-11-18.docx, PM6: confirmed de novo without confirmed paternity and maternity is listed, followed by "Do not use" and the VCEP calibration rationale.
Sources
cspec ↗
PP2 VCEPNot applicable: ENIGMA explicitly does not use PP2 for BRCA1 because benign missense variants are frequent. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1 specification explicitly marks PP2 as not applicable and states that it is not used because BRCA1 has a high frequency of benign missense variants. No PP2 assessment is therefore permitted under this VCEP framework.

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
  • ENIGMA Specifications v1.2, PP2 entry: missense variant in a gene with a low rate of benign missense variation and missense disease mechanism; 'Do not use'; rationale: 'High frequency of benign missense variants.'
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗
PP4 N/ANot applicable: Li et al. reports LR 1.241736334803197, which is within the VCEP's 1.00 to <2.08 non-informative PP4 interval. Details ▾Hide ▴
Reasoning

The governing VCEP permits PP4 only for a combined multifactorial likelihood ratio toward pathogenicity. The exact Li et al. row for BRCA1 c.4481A>G reports LOG(LR)=0.09402938932180405 and LR=1.241736334803197. The VCEP states that a combined LR from 1.00 to <2.08 is not informative and PP4 is not applicable; 1.241736334803197 lies in that interval.

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 ... Combined LR 1.00 to &lt;2.08 is not informative (PP4 not applicable).
Evidence considered
  • Li et al. 2020 Supplementary Table 3, Sheet1, row BRCA1 c.4481A>G: LOG(LR)=0.09402938932180405, N_Probands=2, LR=1.241736334803197.
  • PP4 comparison: 1.241736334803197 ≥ 2.08? no; the VCEP separately defines combined LR 1.00 to <2.08 as not informative, so PP4 is not applicable.
Sources
cspec ↗vcep_pmid_31853058_brca1_clinical_history_lr ↗PMID:31853058 ↗
PP5 VCEPNot applicable: the ENIGMA VCEP explicitly states “Do not use” for PP5. Details ▾Hide ▴
Reasoning

The governing VCEP explicitly says not to use PP5. Therefore, no reputable-source pathogenic assertion is applied under this criterion, regardless of the available ClinVar submissions or literature records.

VCEP rule
Reputable source recently reports variant as pathogenic but the evidence is not available to the laboratory to perform an independent evaluation. ... Do not use
Evidence considered
  • The governing ENIGMA specification lists PP5 as a reputable-source pathogenic report criterion followed by the instruction: Do not use.
Sources
cspec ↗
BP2 VCEPNot applicable: ENIGMA explicitly says BP2 is not used and limits it to the BS2 context. Details ▾Hide ▴
Reasoning

BP2 is explicitly excluded by the ENIGMA BRCA1 VCEP specification: the criterion is not to be used and is applied only in the context of BS2. Therefore BP2 is not applicable regardless of whether any cis/trans co-observation is available.

VCEP rule
Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder, or observed in cis with a pathogenic variant in any inheritance pattern ... Do not use ... Applied only in the context of BS2.
Evidence considered
  • Specifications_V1.2_2024-11-18.docx, Table 1 BP2 row: the criterion is described as observation in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or in cis with a pathogenic variant in any inheritance pattern, followed by 'Do not use' and 'Applied only in the context of BS2.'
  • The CSPEC entry for BP2 marks applicability as 'Not Applicable'.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗
BP3 VCEPNot applicable: the VCEP says Do not use BP3, and c.4481A>G is a missense substitution rather than an in-frame repeat-region insertion or deletion. Details ▾Hide ▴
Reasoning

BP3 is explicitly designated Do not use by the ENIGMA BRCA1/2 specification. Its described variant class is an in-frame deletion or insertion in a repetitive region without known function, whereas this variant is a missense substitution; the VCEP states that the relevant assessment is captured by bioinformatic tool prediction and domain analysis.

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
  • Specifications_V1.2_2024-11-18.docx, Table 1 BP3 row: BP3 is marked Do not use and captured by bioinformatic tool prediction and domain analysis.
  • Appendices_V1.2_2024-11-18.docx, bioinformatic code summary: BP3 is N/A and captured by bioinformatic tool prediction and domain analysis.
  • Case normalization and consequence: NM_007294.4:c.4481A>G, NP_009225.1:p.(Glu1494Gly), missense.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗
BP4 N/ANot applicable: p.Glu1494 lies outside ENIGMA's defined functional domains, so BP4's missense path does not cover this variant. Details ▾Hide ▴
Reasoning

BP4's missense path is restricted by the VCEP to missense or in-frame variants inside a potentially clinically important functional domain and requires both BayesDel no-AF ≤0.15 and SpliceAI ≤0.1. This missense variant affects p.Glu1494, which is outside the VCEP-defined BRCA1 RING aa 2-101, coiled-coil aa 1391-1424, and BRCT aa 1650-1857 domains. It is therefore outside BP4's missense scope, and the predictor values do not change that upstream applicability decision. No variant-level 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 for c.4481A>G, p.Glu1494Gly, or p.E1494G.

VCEP rule
Apply BP4 for 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 predicted No Impact AND SpliceAI ≤0.1).
Evidence considered
  • ENIGMA BRCA1 specification v1.2, BP4 rule: the missense/in-frame path requires a variant inside a potentially clinically important functional domain and BayesDel no-AF ≤0.15 AND SpliceAI ≤0.1.
  • ENIGMA BRCA1 specification v1.2, Appendix J: defined domains are RING aa 2-101, coiled-coil aa 1391-1424, and BRCT repeats aa 1650-1857; p.Glu1494 is outside these intervals.
  • Available predictor values: BayesDel no-AF=-0.107518 and SpliceAI maximum delta=0.122; these were not used to override the upstream domain-scope exclusion.
  • Variant search result: no matching entry for c.4481A>G, p.Glu1494Gly, or p.E1494G in the four governing full-text files named in gaps_remaining.
Still missing
  • No variant-level entry found for c.4481A>G, p.Glu1494Gly, or p.E1494G in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No variant-level entry found for c.4481A>G, p.Glu1494Gly, or p.E1494G in Specifications_V1.2_2024-11-18.docx.txt.
  • No variant-level entry found for c.4481A>G, p.Glu1494Gly, or p.E1494G in Appendices_V1.2_2024-11-18.docx.txt.
  • No variant-level entry found for c.4481A>G, p.Glu1494Gly, or p.E1494G in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗spliceai ↗bayesdel
BP5 N/ANot applicable: LR 1.241736334803197 is not ≤0.48 and lies above the VCEP's informative BP5 range. Details ▾Hide ▴
Reasoning

The governing VCEP limits BP5 to a combined multifactorial likelihood ratio against pathogenicity. The exact Li et al. row for BRCA1 c.4481A>G reports LR=1.241736334803197. The VCEP's BP5 Supporting operator is ≤0.48 and its non-informative interval is >0.48 to 1.00; this value is above 0.48, so the BP5 threshold is not met and the evidence is not an informative BP5 result.

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 &gt;0.23:1 ... Combined LR &gt;0.48-1.00 is not informative (BP5 not applicable)
Evidence considered
  • Li et al. 2020 Supplementary Table 3, Sheet1, row BRCA1 c.4481A>G: LOG(LR)=0.09402938932180405, N_Probands=2, LR=1.241736334803197.
  • BP5 Supporting comparison: 1.241736334803197 ≤ 0.48? no; the VCEP states that combined LR >0.48 to 1.00 is not informative, and this LR is above 1.00, so BP5 is not applicable.
Sources
cspec ↗vcep_pmid_31853058_brca1_clinical_history_lr ↗PMID:31853058 ↗
BP6 VCEPNot applicable: the ENIGMA VCEP explicitly states “Do not use” for BP6. Details ▾Hide ▴
Reasoning

The governing VCEP explicitly says not to use BP6. Therefore, no reputable-source benign assertion is applied under this criterion.

VCEP rule
Reputable source recently reports variant as benign but the evidence is not available to the laboratory to perform an independent evaluation. ... Do not use
Evidence considered
  • The governing ENIGMA specification lists BP6 as a reputable-source benign report criterion followed by the instruction: Do not use.
Sources
cspec ↗
BP7 N/ANot applicable: BP7 covers silent or intronic variants, whereas c.4481A>G is a missense substitution producing p.Glu1494Gly. Details ▾Hide ▴
Reasoning

BP7 is limited by the VCEP to silent variants inside a clinically important functional domain or intronic variants outside conserved donor/acceptor motif positions, and in either case requires BP4. This variant is a missense substitution, not a silent or intronic variant, so BP7 is outside its own scope regardless of the SpliceAI score. No variant-level 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 for c.4481A>G, p.Glu1494Gly, or p.E1494G.

VCEP rule
Apply BP7 for silent variant inside a (potentially) clinically important functional domain, if no predicted impact via splicing (BP4 met). ... Also apply BP7 for intronic variants located outside of conserved donor or acceptor motif positions (at or beyond positions +7/-21), if no predicted impact via splicing (BP4 met).
Evidence considered
  • ENIGMA BRCA1 specification v1.2, BP7 rule: BP7 applies to silent variants inside a clinically important functional domain if BP4 is met, or intronic variants outside conserved donor/acceptor motif positions if BP4 is met.
  • Variant normalization identifies NM_007294.4:c.4481A>G as a missense substitution producing NP_009225.1:p.(Glu1494Gly), so neither BP7 variant-type path applies.
  • SpliceAI maximum delta score=0.122 was recorded but is not relevant to BP7 applicability for this missense variant.
  • Variant search result: no matching entry for c.4481A>G, p.Glu1494Gly, or p.E1494G in the four governing full-text files named in gaps_remaining.
Still missing
  • No variant-level entry found for c.4481A>G, p.Glu1494Gly, or p.E1494G in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No variant-level entry found for c.4481A>G, p.Glu1494Gly, or p.E1494G in Specifications_V1.2_2024-11-18.docx.txt.
  • No variant-level entry found for c.4481A>G, p.Glu1494Gly, or p.E1494G in Appendices_V1.2_2024-11-18.docx.txt.
  • No variant-level entry found for c.4481A>G, p.Glu1494Gly, or p.E1494G in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗spliceai ↗

Identifiers

Gene
BRCA1
Transcript
NM_007294.4
Coding (HGVS c.)
NM_007294.4:c.4481A>G
Protein (HGVS p.)
NP_009225.1:p.(Glu1494Gly)
GRCh38
chr17:43076491 T>C
GRCh37
chr17:41228508 T>C
Location and type
Exon 13 · missense
ClinVar
2774834, 2098260, 1509910, 868434, 481436, 419383, 55228

Gene diagram

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…
gnomAD v4.1 5 / 1,613,712 alleles AF 3.1e-06 · 0 homozygotes · FAF 3.65e-06
gnomAD v2.1 1 / 251,220 alleles AF 3.98e-06 · 0 homozygotes
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 3.1e-06 · 5 / 1,613,712 alleles · 0 hom · FAF 3.7e-06
South Asian2 / 91,074 2.2e-05
European (non-Finnish)3 / 1,179,852 2.5e-06
0 alternate alleles recorded in 8 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American.

gnomAD v2.1

AF 4e-06 · 1 / 251,220 alleles · 0 hom
South Asian1 / 30,612 3.3e-05
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 3.09845e-06; MAF= 0.00031%, 5/1613712 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 2.19602e-05; MAF= 0.00220%, 2/91074 alleles, homozygotes = 0); grpmax FAF= 3.65e-06.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 3.98057e-06; MAF= 0.00040%, 1/251220 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 3.26669e-05; MAF= 0.00327%, 1/30612 alleles, homozygotes = 0).

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +106 bp
0.122
SpliceAI acceptor gainat +98 bp
0.001
SpliceAI donor lossat -3 bp
0.088
SpliceAI donor gainat -32 bp
0.000
Pangolin splice lossmagnitude shown
-0.067
Pangolin splice gain
0.002

Other predictors

REVEL
0.492
BayesDel
-0.108

How the predictions were used

PP3 VCEPNot met: SpliceAI max delta 0.122 is below the ENIGMA PP3 splicing threshold of ≥0.2 for missense variants. Details ▾Hide ▴
Reasoning

The variant is a missense substitution at p.Glu1494Gly (p.E1494G), so the VCEP's missense splicing path is applicable irrespective of functional-domain location. The governing rule requires SpliceAI ≥0.2 for PP3 on this path. The case evidence reports SpliceAI max delta 0.122 (DS_AL 0.122), below the threshold, so PP3 is not met. The BayesDel no-AF score is -0.107518, and residue 1494 is outside the VCEP-defined coiled-coil domain (aa 1391-1424) and BRCT domain (aa 1650-1857); therefore no protein-impact PP3 path applies. No variant-level 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 for c.4481A>G, p.Glu1494Gly, or p.E1494G.

VCEP rule
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
  • ENIGMA BRCA1 specification v1.2, PP3 rule: predicted splicing uses SpliceAI ≥0.2 for silent and missense/in-frame variants irrespective of location in a clinically important functional domain.
  • SpliceAI Lookup for NM_007294.4:c.4481A>G: DS_AG=0.001, DS_AL=0.122, DS_DG=0.000, DS_DL=0.088; maximum delta score=0.122.
  • ENIGMA BRCA1 specification v1.2, Appendix J: protein-impact PP3 for BRCA1 requires BayesDel no-AF ≥0.28 inside a defined clinically important functional domain; the observed score is -0.107518 and p.Glu1494 is outside the defined domains.
  • Variant search result: no matching entry for c.4481A>G, p.Glu1494Gly, or p.E1494G in the four governing full-text files named in gaps_remaining.
Still missing
  • No variant-level entry found for c.4481A>G, p.Glu1494Gly, or p.E1494G in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No variant-level entry found for c.4481A>G, p.Glu1494Gly, or p.E1494G in Specifications_V1.2_2024-11-18.docx.txt.
  • No variant-level entry found for c.4481A>G, p.Glu1494Gly, or p.E1494G in Appendices_V1.2_2024-11-18.docx.txt.
  • No variant-level entry found for c.4481A>G, p.Glu1494Gly, or p.E1494G in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗spliceai ↗bayesdel
BP4 N/ANot applicable: p.Glu1494 lies outside ENIGMA's defined functional domains, so BP4's missense path does not cover this variant. Details ▾Hide ▴
Reasoning

BP4's missense path is restricted by the VCEP to missense or in-frame variants inside a potentially clinically important functional domain and requires both BayesDel no-AF ≤0.15 and SpliceAI ≤0.1. This missense variant affects p.Glu1494, which is outside the VCEP-defined BRCA1 RING aa 2-101, coiled-coil aa 1391-1424, and BRCT aa 1650-1857 domains. It is therefore outside BP4's missense scope, and the predictor values do not change that upstream applicability decision. No variant-level 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 for c.4481A>G, p.Glu1494Gly, or p.E1494G.

VCEP rule
Apply BP4 for 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 predicted No Impact AND SpliceAI ≤0.1).
Evidence considered
  • ENIGMA BRCA1 specification v1.2, BP4 rule: the missense/in-frame path requires a variant inside a potentially clinically important functional domain and BayesDel no-AF ≤0.15 AND SpliceAI ≤0.1.
  • ENIGMA BRCA1 specification v1.2, Appendix J: defined domains are RING aa 2-101, coiled-coil aa 1391-1424, and BRCT repeats aa 1650-1857; p.Glu1494 is outside these intervals.
  • Available predictor values: BayesDel no-AF=-0.107518 and SpliceAI maximum delta=0.122; these were not used to override the upstream domain-scope exclusion.
  • Variant search result: no matching entry for c.4481A>G, p.Glu1494Gly, or p.E1494G in the four governing full-text files named in gaps_remaining.
Still missing
  • No variant-level entry found for c.4481A>G, p.Glu1494Gly, or p.E1494G in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No variant-level entry found for c.4481A>G, p.Glu1494Gly, or p.E1494G in Specifications_V1.2_2024-11-18.docx.txt.
  • No variant-level entry found for c.4481A>G, p.Glu1494Gly, or p.E1494G in Appendices_V1.2_2024-11-18.docx.txt.
  • No variant-level entry found for c.4481A>G, p.Glu1494Gly, or p.E1494G in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗spliceai ↗bayesdel
BP7 N/ANot applicable: BP7 covers silent or intronic variants, whereas c.4481A>G is a missense substitution producing p.Glu1494Gly. Details ▾Hide ▴
Reasoning

BP7 is limited by the VCEP to silent variants inside a clinically important functional domain or intronic variants outside conserved donor/acceptor motif positions, and in either case requires BP4. This variant is a missense substitution, not a silent or intronic variant, so BP7 is outside its own scope regardless of the SpliceAI score. No variant-level 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 for c.4481A>G, p.Glu1494Gly, or p.E1494G.

VCEP rule
Apply BP7 for silent variant inside a (potentially) clinically important functional domain, if no predicted impact via splicing (BP4 met). ... Also apply BP7 for intronic variants located outside of conserved donor or acceptor motif positions (at or beyond positions +7/-21), if no predicted impact via splicing (BP4 met).
Evidence considered
  • ENIGMA BRCA1 specification v1.2, BP7 rule: BP7 applies to silent variants inside a clinically important functional domain if BP4 is met, or intronic variants outside conserved donor/acceptor motif positions if BP4 is met.
  • Variant normalization identifies NM_007294.4:c.4481A>G as a missense substitution producing NP_009225.1:p.(Glu1494Gly), so neither BP7 variant-type path applies.
  • SpliceAI maximum delta score=0.122 was recorded but is not relevant to BP7 applicability for this missense variant.
  • Variant search result: no matching entry for c.4481A>G, p.Glu1494Gly, or p.E1494G in the four governing full-text files named in gaps_remaining.
Still missing
  • No variant-level entry found for c.4481A>G, p.Glu1494Gly, or p.E1494G in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No variant-level entry found for c.4481A>G, p.Glu1494Gly, or p.E1494G in Specifications_V1.2_2024-11-18.docx.txt.
  • No variant-level entry found for c.4481A>G, p.Glu1494Gly, or p.E1494G in Appendices_V1.2_2024-11-18.docx.txt.
  • No variant-level entry found for c.4481A>G, p.Glu1494Gly, or p.E1494G in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗spliceai ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.12). REVEL score = 0.492. BayesDel score = -0.107518.

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

  • Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
    No paper-specific finding is recorded.
    PMID 25741868 ↗
  • American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography.
    Saslow D et al. · 2007
    No paper-specific finding is recorded.
    PMID 17392385 ↗
  • NSGC practice guideline: risk assessment and genetic counseling for hereditary breast and ovarian cancer.
    No paper-specific finding is recorded.
    PMID 23188549 ↗
  • Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women: U.S. Preventive Services Task Force recommendation statement.
    No paper-specific finding is recorded.
    PMID 24366376 ↗
  • PMID 24432435
    No paper-specific finding is recorded.
    PMID 24432435 ↗
  • American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers.
    No paper-specific finding is recorded.
    PMID 24493721 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 5 / 1,613,712 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.122 Open source ↗
ClinVar 4 Uncertain significance · 1 Uncertain Significance Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗
ClinGen CSpec Captured ClinGen CSpec source record Open source ↗

All source links

Statements for reports

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= 3.09845e-06; MAF= 0.00031%, 5/1613712 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 2.19602e-05; MAF= 0.00220%, 2/91074 alleles, homozygotes = 0); grpmax FAF= 3.65e-06.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 3.98057e-06; MAF= 0.00040%, 1/251220 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 3.26669e-05; MAF= 0.00327%, 1/30612 alleles, homozygotes = 0).

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Uncertain significance (4 clinical laboratories) and as Uncertain Significance (1 clinical laboratory). (ClinVarID = 481436)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.12). REVEL score = 0.492. BayesDel score = -0.107518.

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.