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BRCA1c.4331delPathogenic
Print report
Variant interpretation report

BRCA1 c.4331del, p.(Asn1444IlefsTer12)

NM_007294.4:c.4331del NP_009225.1:p.(Asn1444IlefsTer12) Frameshift · exon 12 View identifiers
Classification
Pathogenic

Variant description:

No variant summary was recorded for this case.

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

Pathogenic.A pathogenic classification under the recorded framework.

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: 2 Benign evidence criteria: 0
Pathogenic criteria applied · 2
PVS1Very strong
PVS1 · very strong

Met, very strong: the exon E12(13) Table 4 row assigns PVS1 to coding PTC variants, and c.4331del creates p.Asn1444IlefsTer12 in a 1864-residue protein.

PM5Strong
PM5 · strong

Met, strong: ENIGMA Table 4 assigns PM5_Strong (PTC) to BRCA1 exon 12(13), where c.4331del creates a p.1455 termination.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Pathogenic

Pathogenic: ENIGMA Table 3 classifies one very strong criterion plus one strong criterion as Pathogenic, here PVS1 (very strong) and PM5 (strong).

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.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

No listed criterion applied
gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗
SpliceAI score
0.007 maximum delta

Recorded SpliceAI maximum delta score: 0.007. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

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: 2 met · 2 not met · 11 not assessed · 13 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

The governing ENIGMA BRCA1/2 VCEP specification is applicable to the MANE transcript NM_007294.4 and takes precedence over generic ACMG/AMP rules.

For this group, the applicable evidence is PVS1 at very strong strength; PM4 and BP3 are not applicable under the VCEP framework.

PS2 and PM6 are not applicable because the governing ENIGMA BRCA1/2 VCEP specification explicitly prohibits both de novo criteria.

PP1 and BS4 remain not assessed because the available case evidence contains no quantitative family segregation or non-segregation data.

The ENIGMA BRCA1/2 VCEP specification governs both criteria: PM3 requires Fanconi-anemia phenotype with same-gene pathogenic/likely pathogenic co-occurrence, while BP2 is explicitly not used except within BS2.

No qualifying PM3 phase, partner-variant, or affected-proband evidence was documented for NM_007294.4:c.4331del, so PM3 remains not assessed rather than being inferred from the variant's truncating consequence.

Population evidence was adjudicated under the ENIGMA BRCA1 VCEP specification, which takes precedence over generic ACMG thresholds.

The specified non-cancer datasets were used for the population rules: gnomAD v2.1 non-cancer exomes and gnomAD v3.1 non-cancer genomes. The variant was absent from both; all-comers gnomAD v2.1 and v4.1 also reported absence.

No benign frequency code is met, PM2 is excluded because the variant is a deletion, and BS2 remains unassessed because no qualifying clinical-proband observations were available.

Met · 2

PVS1 Very strongMet, very strong: the exon E12(13) Table 4 row assigns PVS1 to coding PTC variants, and c.4331del creates p.Asn1444IlefsTer12 in a 1864-residue protein. Details ▾Hide ▴
Reasoning

NM_007294.4:c.4331del is a frameshift producing NP_009225.1:p.(Asn1444IlefsTer12), truncating the 1864-residue BRCA1 protein at predicted residue 1455. Variant Validator places c.4331 in exon 12 of the MANE transcript, corresponding to ENIGMA legacy exon E12(13), whose governing Table 4 row assigns PVS1 to coding PTC variants and identifies the predicted PTC/NMD framework for this exon. The ENIGMA BRCA1/2 specification establishes loss of function as a disease mechanism and directs exon-specific PVS1 application; this variant is not in a terminal exon and the predicted premature termination is well upstream of the intact BRCT domain, so no named downgrade rule applies. The Table 4 pre-assigned PVS1 decision outranks generic thresholds.

Rule
ENIGMA BRCA1/2 Specification v1.2, Specifications Table 4: coding frameshift/PTC variant in BRCA1 legacy exon E12(13) receives PVS1; no specific downgrade rule applies.
Evidence considered
  • The ENIGMA BRCA1/2 specification defines PVS1 as variable-weight evidence for null variants in genes where loss of function is a known disease mechanism and directs use of the exon-organized Table 4 decision tree.
  • Specifications_Table4_V1.2_2024-11-18.xlsx.txt, row E12(13), assigns PVS1 to coding PTC variants and labels the relevant exon PTC/NMD framework as PVS1.
  • The case normalization identifies NM_007294.4:c.4331del as a frameshift, NP_009225.1:p.(Asn1444IlefsTer12), with predicted protein residue range ending at 1455 versus original length 1864; Variant Validator places the variant in exon 12.
  • The ENIGMA specification states that PM5 (PTC) exon weights assume the molecular effect of PTC variants predicted to lead to NMD, and its PVS1 framework applies to genomic nonsense and frameshift changes.
Still missing
  • No exact entry for c.4331del, p.Asn1444IlefsTer12, or p.N1444Ifs*12 was found when searching Specifications_Table4_V1.2_2024-11-18.xlsx.txt.
  • No exact entry for c.4331del, p.Asn1444IlefsTer12, or p.N1444Ifs*12 was found when searching Specifications_V1.2_2024-11-18.docx.txt.
  • No exact entry for c.4331del, p.Asn1444IlefsTer12, or p.N1444Ifs*12 was found when searching Appendices_V1.2_2024-11-18.docx.txt.
  • No exact entry for c.4331del, p.Asn1444IlefsTer12, or p.N1444Ifs*12 was found when searching PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗vcep_specifications_table4_v1_2_2024_11_18vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18
PM5 StrongMet, strong: ENIGMA Table 4 assigns PM5_Strong (PTC) to BRCA1 exon 12(13), where c.4331del creates a p.1455 termination. Details ▾Hide ▴
Reasoning

PM5 is met at strong strength under the ENIGMA repurposed PM5_PTC rule. The case is a frameshift, c.4331del, producing a premature termination codon at p.1455. Specifications_Table4 places c.4331 within BRCA1 exon 12(13), and its exon 12(13) row assigns PVS1 for PTC variants and PM5_Strong (PTC); the file's readme states that PM5_PTC is applicable when Column L is not PM5_N/A. Exon 12(13) is explicitly among the PM5_PTC-applicable exons, while the excluded PM5_N/A exons are E21(22), E6(7), and E7(8). This is the governing pre-assigned exon-level code and outranks any generic same-residue missense PM5 analysis.

Rule
ENIGMA BRCA1/2 V1.2 PM5_VariableWeight (PTC): apply the pre-assigned exon-specific PM5_PTC weight for a protein-termination variant; Table 4 assigns PM5_Strong (PTC) to E12(13).
Evidence considered
  • Specifications_Table4 assigns the BRCA1 exon 12(13) PTC row PM5_Strong (PTC); exon 12(13) spans c.4186-c.4357 and therefore contains c.4331.
  • The Table 4 readme defines PM5_PTC as applicable when the exon is not marked PM5_N/A and lists E12(13) among the PM5_PTC-applicable exons.
  • The normalized consequence is p.(Asn1444IlefsTer12), with predicted termination at amino acid 1455.
Sources
vcep_specifications_table4_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18

Not met · 2 · evaluated, threshold not reached

BA1 Not met: the variant was absent from gnomAD v2.1 and v4.1, so no non-founder filter allele frequency exceeded the ENIGMA BA1 threshold of 0.001. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1 VCEP requires BA1 when the maximum filter allele frequency exceeds 0.001 in a non-founder population, using gnomAD v2.1 non-cancer exomes and/or gnomAD v3.1 non-cancer genomes, with adequate read depth. The variant was absent from gnomAD v2.1 and gnomAD v4.1, and the case evidence specifically records absence from gnomAD v2.1 non-cancer and gnomAD v3.1 non-cancer; therefore no allele frequency exceeds the BA1 threshold. The deletion is not a pathogenic founder variant for purposes of this rule, and no read-depth failure was reported.

Rule
Filter allele frequency (FAF) > 0.001 in gnomAD v2.1 non-cancer exomes and/or gnomAD v3.1 non-cancer genomes, in non-founder populations; do not apply if read depth <20 or for a well-established pathogenic founder variant.
Evidence considered
  • ENIGMA BRCA1 VCEP BA1 rule: apply stand-alone benign evidence when filter allele frequency is above 0.001 in gnomAD v2.1 non-cancer exomes and/or gnomAD v3.1 non-cancer genomes, assessed in non-founder populations and separately by exome/genome dataset.
  • The case evidence records the variant as absent from gnomAD v2.1, gnomAD v4.1, gnomAD v2.1 non-cancer, and gnomAD v3.1 non-cancer; therefore the observed maximum frequency is 0 and does not exceed 0.001.
Still missing
  • No exact c.4331del, p.Asn1444IlefsTer12, or p.N1444Ifs*12 entry was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No exact c.4331del, p.Asn1444IlefsTer12, or p.N1444Ifs*12 entry was found in HUMU-40-1557-s001.xlsx.txt.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗
BS1 Not met: the variant was absent from both specified non-cancer gnomAD datasets, giving frequency 0 below the ENIGMA BS1 Supporting threshold of 0.00002. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1 VCEP assigns BS1 Strong when filter allele frequency is above 0.0001 and BS1 Supporting when it is above 0.00002 through 0.0001, using gnomAD v2.1 non-cancer exomes and/or gnomAD v3.1 non-cancer genomes in non-founder populations. The variant was absent from both specified non-cancer datasets and from the all-comers gnomAD v2.1 and v4.1 records, so the observed frequency is 0 and meets neither BS1 threshold.

Rule
Use maximum filter allele frequency in a non-founder population, separately for gnomAD v2.1 non-cancer exomes and gnomAD v3.1 non-cancer genomes; BS1 Strong >0.0001, BS1 Supporting >0.00002 and <=0.0001; do not apply if read depth <20 or for a well-established pathogenic founder variant.
Evidence considered
  • ENIGMA BRCA1 VCEP BS1 rule: BS1 Strong requires filter allele frequency >0.0001; BS1 Supporting requires >0.00002 and <=0.0001, in gnomAD v2.1 non-cancer exomes and/or gnomAD v3.1 non-cancer genomes.
  • The case evidence records absence from gnomAD v2.1 non-cancer and gnomAD v3.1 non-cancer, so the maximum observed allele frequency is 0 and below both BS1 thresholds.
Still missing
  • No exact c.4331del, p.Asn1444IlefsTer12, or p.N1444Ifs*12 entry was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No exact c.4331del, p.Asn1444IlefsTer12, or p.N1444Ifs*12 entry was found in HUMU-40-1557-s001.xlsx.txt.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗

Not assessed · 11 · no assessment recorded

PS3 Not assessed: no variant-specific calibrated assay result or pre-assigned PS3 code was found for c.4331del or p.Asn1444IlefsTer12. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1/2 VCEP specification requires PS3 functional evidence to come from well-established protein-only or combined mRNA/protein assays, with calibrated variant-specific recommendations in Specifications Table 9. The governing VCEP files were searched under c.4331del, p.Asn1444IlefsTer12, and p.N1444Ifs*12; no entry or pre-assigned PS3 code was found. The case's fetched functional-theme publications (PMIDs 11358863, 12483515, 12947386, and 20608970) do not mention this variant and provide only general BRCA1 or non-equivalent truncation-model evidence. Therefore, no variant-specific validated assay result supports PS3, and PS3 is not assessed.

Rule
ENIGMA BRCA1/2 VCEP v1.2 PS3: apply only for well-established functional studies supportive of a damaging effect measured via protein alone or mRNA and protein combined; use Table 9 calibrated variant-specific recommendations where available.
Evidence considered
  • ENIGMA VCEP v1.2 states that PS3 applies to well-established functional studies measuring protein function alone or mRNA plus protein, and directs calibrated variant-specific recommendations to Specifications Table 9.
  • The exact variant notations c.4331del, p.Asn1444IlefsTer12, and p.N1444Ifs*12 were searched in all five declared governing VCEP full-text files without a matching functional-assay row or pre-assigned PS3 code.
  • PMID:11358863 reports a distinct engineered mouse Brca1 truncating allele, not this human variant; PMID:12483515 and PMID:12947386 are general BRCA1/BRCA2 functional reviews; PMID:20608970 is a general review of BRCA1 truncating mutations. None supplies variant-specific assay evidence for c.4331del.
Still missing
  • Specifications_Table9_V1.2_2024-11-18.xlsx.txt: no entry found for c.4331del, p.Asn1444IlefsTer12, or p.N1444Ifs*12.
  • SupplementaryTables_V1.2_2024-11-18.xlsx.txt: no entry found for c.4331del, p.Asn1444IlefsTer12, or p.N1444Ifs*12.
  • Specifications_V1.2_2024-11-18.docx.txt: no variant-specific functional assay entry found for c.4331del, p.Asn1444IlefsTer12, or p.N1444Ifs*12.
  • Appendices_V1.2_2024-11-18.docx.txt: no variant-specific functional assay entry found for c.4331del, p.Asn1444IlefsTer12, or p.N1444Ifs*12.
  • HUMU-40-1557-s001.xlsx.txt: no entry found for c.4331del, p.Asn1444IlefsTer12, or p.N1444Ifs*12.
  • No fetched publication provides a variant-specific validated protein or combined mRNA/protein assay result for this variant.
Sources
cspec ↗vcep_specifications_table9_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18vcep_humu_40_1557_s001PMID:11358863 ↗PMID:12483515 ↗PMID:12947386 ↗PMID:20608970 ↗
PS4 Not assessed: no case-control p-value, OR, or confidence interval is available for comparison with p-value <=0.05 and OR >=4. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1 specification requires case-control evidence with p-value <=0.05 and OR >=4, with the lower confidence interval excluding 2.0. The case bundle contains no case-control counts, odds ratio, confidence interval, p-value, or validated proband-counting evidence; the specification explicitly says not to use proband counting as originally described. Therefore PS4 cannot be assessed.

Rule
Case-control studies; p-value <=0.05 and OR >=4 (lower confidence interval excludes 2.0). Proband counting as originally described is not used.
Evidence considered
  • ENIGMA Specifications_V1.2_2024-11-18.docx states: 'Case-control studies; p-value <=0.05 and OR >=4 (lower confidence interval excludes 2.0).'
  • The same specification states that the case dataset should be ethnicity and country-matched to the control dataset and that proband counting should not be used as originally described.
  • No exact-variant entry was found when searching Specifications_V1.2_2024-11-18.docx.txt for c.4331del, p.Asn1444IlefsTer12, and p.N1444Ifs*12.
Still missing
  • No case-control dataset, p-value, odds ratio, or lower confidence interval was provided.
  • No usable ethnicity- and country-matched case-control analysis was provided.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
PM3 Not assessed: no documented Fanconi-anemia phenotype, same-gene pathogenic partner, affected-proband observation, or phase evidence was available to reach the ENIGMA PM3 point thresholds. Details ▾Hide ▴
Reasoning

The governing ENIGMA BRCA1/2 specification restricts PM3_VariableWeight to patients with phenotype consistent with BRCA1- or BRCA2-related Fanconi anemia and a pathogenic or likely pathogenic co-occurring variant in the same gene. It assigns 2 points for a confirmed or inferred pathogenic/likely pathogenic variant in trans or homozygous, 1 point when phase is unknown, and final strengths of PM3_Supporting at 1 point, PM3 at 2 points, and PM3_Strong at 4 or more points. The case evidence reviewed for NM_007294.4:c.4331del / p.(Asn1444IlefsTer12) contains no documented Fanconi-anemia phenotype, affected-proband observation meeting those criteria, co-occurring BRCA1 pathogenic/likely pathogenic variant, or phase evidence. The governing Specifications_V1.2_2024-11-18.docx was searched for c.4331del, p.Asn1444IlefsTer12, and p.N1444Ifs*12; no variant-specific PM3 entry was found. PM3 therefore cannot be assigned from the available evidence.

Rule
ENIGMA PM3_VariableWeight: phenotype consistent with BRCA1/2-related Fanconi anemia plus a same-gene pathogenic/likely pathogenic co-occurring variant; PM3_Supporting = 1 point, PM3 = 2 points, PM3_Strong = 4 or more points.
Evidence considered
  • ENIGMA BRCA1/2 Specifications v1.2, Table 1 and Table 6: PM3_VariableWeight applies only with a BRCA1/2-related Fanconi-anemia phenotype and same-gene pathogenic/likely pathogenic co-occurrence; 1, 2, and 4 or more points correspond to supporting, moderate, and strong PM3, respectively.
  • The reviewed case evidence documents the variant as NM_007294.4:c.4331del, predicted p.(Asn1444IlefsTer12), but provides no qualifying Fanconi-anemia phenotype, same-gene pathogenic partner, or phase assignment.
  • Specifications_V1.2_2024-11-18.docx was searched for c.4331del, p.Asn1444IlefsTer12, and p.N1444Ifs*12; no variant-specific PM3 entry was found.
Still missing
  • No documented Fanconi-anemia phenotype or chromosome-breakage result for an affected proband.
  • No documented co-occurring BRCA1 pathogenic or likely pathogenic variant in the same proband.
  • No parental genotyping, segregation data, or other evidence establishing trans, cis, homozygous, or unknown phase.
  • No variant-specific PM3 entry was found in Specifications_V1.2_2024-11-18.docx after searching c.4331del, p.Asn1444IlefsTer12, and p.N1444Ifs*12.
Sources
cspec ↗
PP1 Not assessed: no quantitative cosegregation LR or affected-family meioses are provided to compare with the ENIGMA PP1 supporting threshold of LR >=2.08:1. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1/2 VCEP specification permits PP1 only for quantitative cosegregation with disease in multiple affected family members. It assigns PP1 supporting at LR >=2.08:1, PP1 moderate at LR >=4.3:1, PP1 strong at LR >=18.7:1, and PP1 very strong at LR >=350:1. The case evidence bundle provides no affected-family meioses, phenotype-linked segregation observations, parental/relative genotypes, or quantitative cosegregation LR, so no PP1 strength can be assigned. Searches of Specifications_V1.2_2024-11-18.docx.txt and HUMU-40-1557-s001.xlsx.txt found no entry for c.4331del, p.Asn1444IlefsTer12, or p.N1444Ifs*12.

Rule
ENIGMA BRCA1/2 VCEP v1.2 PP1: quantitative cosegregation with disease; supporting LR >=2.08:1, moderate LR >=4.3:1, strong LR >=18.7:1, very strong LR >=350:1.
Evidence considered
  • ENIGMA BRCA1/2 VCEP v1.2 requires quantitative cosegregation analysis for PP1 and defines thresholds of LR >=2.08:1 supporting, >=4.3:1 moderate, >=18.7:1 strong, and >=350:1 very strong.
  • The consolidated case-evidence bundle contains no usable family segregation, meiosis, parental-testing, phenotype-linked genotype, or cosegregation-LR result for this variant.
Still missing
  • No affected-family segregation observations, phenotype details, parental or relative genotypes, or quantitative cosegregation LR are present in the case evidence bundle.
  • No entry for c.4331del, p.Asn1444IlefsTer12, or p.N1444Ifs*12 was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No entry for c.4331del, p.Asn1444IlefsTer12, or p.N1444Ifs*12 was found in HUMU-40-1557-s001.xlsx.txt.
Sources
cspec ↗
PP4 Not assessed: no exact-variant combined clinical LR is available for comparison with the PP4 Supporting threshold LR >=2.08:1. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1 specification limits PP4 to a combined, clinically calibrated likelihood ratio toward pathogenicity. Its literal thresholds are PP4 Supporting LR >=2.08:1, Moderate LR >=4.3:1, Strong LR >=18.7:1, and Very Strong LR >=350:1; combined LR from 1.00 to <2.08 is not informative. The gene-specific clinical-history LR table contains no exact BRCA1 c.4331del, p.Asn1444IlefsTer12, or p.N1444Ifs*12 entry, and no combined clinical LR is supplied, so PP4 cannot be assessed.

Rule
Use only combined clinically calibrated LR toward pathogenicity: Supporting LR >=2.08:1; Moderate LR >=4.3:1; Strong LR >=18.7:1; Very Strong LR >=350:1.
Evidence considered
  • ENIGMA Specifications_V1.2_2024-11-18.docx states that PP4 is used only for combined LR toward pathogenicity based on multifactorial clinical data, with thresholds LR >=2.08:1, >=4.3:1, >=18.7:1, and >=350:1 for Supporting, Moderate, Strong, and Very Strong, respectively.
  • The specification states that combined LR from 1.00 to <2.08 is not informative and that clinical data may include co-segregation, co-occurrence, family history, tumour pathology, and case-control data.
  • PMID_31853058_BRCA1_clinical_history_LR.xlsx.txt was searched for c.4331del, p.Asn1444IlefsTer12, and p.N1444Ifs*12; no exact-variant row was found.
  • PMID:31853058 and PMID:17924331 were consulted as methodology/context sources, not as substitutes for an exact-variant clinical LR entry.
Still missing
  • No exact BRCA1 c.4331del entry was found in PMID_31853058_BRCA1_clinical_history_LR.xlsx.txt.
  • No combined multifactorial clinical likelihood ratio or component likelihood ratios were provided.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18vcep_pmid_31853058_brca1_clinical_history_lrPMID:31853058 ↗PMID:17924331 ↗
PP5 Not assessed: ClinVar has no exact-variant expert-panel pathogenic or likely pathogenic classification, and ENIGMA marks PP5 as not for use. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1 specification says PP5 is not to be used. Independently, the required exact-variant ClinVar expert-panel trigger is absent: the case evidence reports no ClinVar record, no expert-panel classification, and no submissions. Therefore there is no qualifying pathogenic or likely pathogenic expert-panel assertion for PP5.

Rule
Apply only to an exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification; ENIGMA BRCA1 specifies PP5 is not for use.
Evidence considered
  • ENIGMA Specifications_V1.2_2024-11-18.docx states for PP5: 'Do not use.'
  • The case ClinVar evidence reports no result, and clinvar_submission_audit.json is empty; therefore no exact-variant expert-panel pathogenic or likely pathogenic assertion is available.
  • The OncoKB record is not a ClinVar expert-panel classification and cannot trigger PP5 under the requested rule.
Still missing
  • No exact-variant ClinVar expert-panel classification is available; the case ClinVar result is no result found.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18clinvar ↗
BS2 Not assessed: no qualifying healthy-adult, homozygous, phase, age, follow-up, or Fanconi Anemia data were available for the ENIGMA BS2 point system. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1 VCEP applies BS2 using points from clinical or research probands who are homozygous, in trans with a pathogenic or likely pathogenic variant, or phase-unknown with such a variant, and who meet the specified age or cancer-unaffected follow-up criteria without a Fanconi Anemia phenotype. The available population evidence documents absence from gnomAD but does not provide qualifying healthy-adult clinical observations, zygosity, phase, age, follow-up, or Fanconi Anemia assessment. Homozygote observations in gnomAD cannot substitute for the required phenotyped-proband evidence and are not available here.

Rule
Apply only in the context of BS2 Table 8/Appendix H point scoring for qualifying clinical or research probands; homozygote observations in gnomAD are not used for this code. BS2 requires >=4 points.
Evidence considered
  • ENIGMA BRCA1 VCEP BS2 requires point-scored observations in clinical or research probands: for example, a homozygote with a patient cancer onset over 50 years or cancer-unaffected follow-up over 50 years contributes 2 points, with final BS2 requiring at least 4 points.
  • The case evidence contains population absence results only and no qualifying proband-level BS2 observations; gnomAD frequency data are explicitly not to be used as the BS2 clinical-proband evidence.
Still missing
  • No qualifying clinical or research proband data were found for BS2, including zygosity or phase, age at cancer diagnosis or last follow-up, and Fanconi Anemia phenotype assessment.
  • No exact c.4331del, p.Asn1444IlefsTer12, or p.N1444Ifs*12 entry was found in Appendices_V1.2_2024-11-18.docx.txt.
Sources
cspec ↗
BS3 Not assessed: no variant-specific calibrated benign assay result or pre-assigned BS3 code was found for c.4331del or p.Asn1444IlefsTer12. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1/2 VCEP specification requires BS3 evidence to come from well-established assays showing no damaging effect on protein function, measured via protein alone or combined mRNA/protein, with calibrated variant-specific recommendations in Specifications Table 9. The governing VCEP files were searched under c.4331del, p.Asn1444IlefsTer12, and p.N1444Ifs*12; no entry or pre-assigned BS3 code was found. The case's fetched functional-theme publications do not mention this variant and do not provide a benign variant-specific assay result or assay controls for it. Therefore, BS3 is not assessed.

Rule
ENIGMA BRCA1/2 VCEP v1.2 BS3: apply only for well-established functional studies showing no damaging effect on protein function measured via protein alone or mRNA and protein combined; use Table 9 calibrated variant-specific recommendations where available.
Evidence considered
  • ENIGMA VCEP v1.2 states that BS3 applies to well-established functional studies showing no damaging effect on protein function measured via protein alone or mRNA plus protein, and directs calibrated variant-specific recommendations to Specifications Table 9.
  • The exact variant notations c.4331del, p.Asn1444IlefsTer12, and p.N1444Ifs*12 were searched in all five declared governing VCEP full-text files without a matching functional-assay row or pre-assigned BS3 code.
  • PMID:11358863, PMID:12483515, PMID:12947386, and PMID:20608970 do not mention this variant and provide no variant-specific benign assay result or assay-control evidence that could support BS3.
Still missing
  • Specifications_Table9_V1.2_2024-11-18.xlsx.txt: no entry found for c.4331del, p.Asn1444IlefsTer12, or p.N1444Ifs*12.
  • SupplementaryTables_V1.2_2024-11-18.xlsx.txt: no entry found for c.4331del, p.Asn1444IlefsTer12, or p.N1444Ifs*12.
  • Specifications_V1.2_2024-11-18.docx.txt: no variant-specific functional assay entry found for c.4331del, p.Asn1444IlefsTer12, or p.N1444Ifs*12.
  • Appendices_V1.2_2024-11-18.docx.txt: no variant-specific functional assay entry found for c.4331del, p.Asn1444IlefsTer12, or p.N1444Ifs*12.
  • HUMU-40-1557-s001.xlsx.txt: no entry found for c.4331del, p.Asn1444IlefsTer12, or p.N1444Ifs*12.
  • No fetched publication provides a variant-specific validated benign protein or combined mRNA/protein assay result with relevant controls for this variant.
Sources
cspec ↗vcep_specifications_table9_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18vcep_humu_40_1557_s001PMID:11358863 ↗PMID:12483515 ↗PMID:12947386 ↗PMID:20608970 ↗
BS4 Not assessed: no quantitative non-segregation LR or affected relatives lacking the variant are provided to compare with the ENIGMA BS4 supporting threshold of LR <=0.48:1. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1/2 VCEP specification permits BS4 only for quantitative lack of segregation in affected family members. It assigns BS4 supporting at LR <=0.48:1, BS4 moderate at LR <=0.23:1, BS4 strong at LR <=0.05:1, and BS4 very strong at LR <=0.00285:1. The case evidence bundle provides no affected relatives lacking the variant, non-segregation observations, parental/relative genotypes, or quantitative non-segregation LR, so no BS4 strength can be assigned. Searches of Specifications_V1.2_2024-11-18.docx.txt and HUMU-40-1557-s001.xlsx.txt found no entry for c.4331del, p.Asn1444IlefsTer12, or p.N1444Ifs*12.

Rule
ENIGMA BRCA1/2 VCEP v1.2 BS4: quantitative lack of segregation in affected family members; supporting LR <=0.48:1, moderate LR <=0.23:1, strong LR <=0.05:1, very strong LR <=0.00285:1.
Evidence considered
  • ENIGMA BRCA1/2 VCEP v1.2 requires quantitative lack-of-segregation analysis for BS4 and defines thresholds of LR <=0.48:1 supporting, <=0.23:1 moderate, <=0.05:1 strong, and <=0.00285:1 very strong.
  • The consolidated case-evidence bundle contains no usable affected-relative non-segregation, meiosis, parental-testing, phenotype-linked genotype, or BS4 likelihood-ratio result for this variant.
Still missing
  • No affected relatives lacking the variant, non-segregation observations, parental or relative genotypes, or quantitative non-segregation LR are present in the case evidence bundle.
  • No entry for c.4331del, p.Asn1444IlefsTer12, or p.N1444Ifs*12 was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No entry for c.4331del, p.Asn1444IlefsTer12, or p.N1444Ifs*12 was found in HUMU-40-1557-s001.xlsx.txt.
Sources
cspec ↗
BP5 Not assessed: no exact-variant combined clinical LR is available for comparison with the BP5 Supporting interval LR <=0.48 and >0.23. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1 specification restricts BP5 to a combined, clinically calibrated likelihood ratio against pathogenicity. The literal operators are BP5 Very Strong LR <=0.00285:1, Strong LR <=0.05:1, Moderate LR <=0.23:1, and Supporting LR <=0.48 to >0.23:1; combined LR >0.48-1.00 is not informative. No exact-variant clinical-history LR row or combined LR is available, so no inequality can be evaluated and BP5 cannot be assessed.

Rule
Use only combined clinically calibrated LR against pathogenicity: Very Strong LR <=0.00285:1; Strong LR <=0.05:1; Moderate LR <=0.23:1; Supporting LR <=0.48 to >0.23:1.
Evidence considered
  • ENIGMA Specifications_V1.2_2024-11-18.docx states BP5 is used only for combined LR against pathogenicity and gives the literal thresholds LR <=0.00285:1, <=0.05:1, <=0.23:1, and <=0.48 to >0.23:1 for Very Strong, Strong, Moderate, and Supporting, respectively.
  • The specification states that combined LR >0.48-1.00 is not informative for BP5.
  • PMID_31853058_BRCA1_clinical_history_LR.xlsx.txt was searched for c.4331del, p.Asn1444IlefsTer12, and p.N1444Ifs*12; no exact-variant row was found.
  • PMID:31853058 and PMID:17924331 were consulted as methodology/context sources, not as substitutes for an exact-variant clinical LR entry.
Still missing
  • No exact BRCA1 c.4331del entry was found in PMID_31853058_BRCA1_clinical_history_LR.xlsx.txt.
  • No combined multifactorial clinical likelihood ratio or component likelihood ratios were provided.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18vcep_pmid_31853058_brca1_clinical_history_lrPMID:31853058 ↗PMID:17924331 ↗
BP6 Not assessed: ClinVar has no exact-variant expert-panel benign or likely benign classification, and ENIGMA marks BP6 as not for use. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1 specification says BP6 is not to be used. Independently, the required exact-variant ClinVar expert-panel trigger is absent: the case evidence reports no ClinVar record, no expert-panel classification, and no submissions. Therefore there is no qualifying benign or likely benign expert-panel assertion for BP6.

Rule
Apply only to an exact-variant ClinVar expert-panel Benign or Likely benign classification; ENIGMA BRCA1 specifies BP6 is not for use.
Evidence considered
  • ENIGMA Specifications_V1.2_2024-11-18.docx states for BP6: 'Do not use.'
  • The case ClinVar evidence reports no result, and clinvar_submission_audit.json is empty; therefore no exact-variant expert-panel benign or likely benign assertion is available.
  • No ordinary laboratory submission, aggregate ClinVar label, or non-expert assertion was used to trigger BP6.
Still missing
  • No exact-variant ClinVar expert-panel classification is available; the case ClinVar result is no result found.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18clinvar ↗
Not applicable · 13· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/ANot applicable: c.4331del is a frameshift, whereas ENIGMA PS1 requires a same-protein missense change or precisely matching splice event. Details ▾Hide ▴
Reasoning

PS1 is not applicable because NM_007294.4:c.4331del is a frameshift producing p.(Asn1444IlefsTer12), not a missense substitution or a variant with a demonstrated matching splice event. The ENIGMA specification restricts PS1 to a same-protein missense change caused by a different nucleotide change, or to a precisely matching splice consequence. Direct searches for c.4331del, p.Asn1444IlefsTer12, and p.N1444Ifs*12 found no entry in Specifications_Table4_V1.2_2024-11-18.xlsx.txt, SupplementaryTables_V1.2_2024-11-18.xlsx.txt, Specifications_V1.2_2024-11-18.docx.txt, or Appendices_V1.2_2024-11-18.docx.txt.

Rule
ENIGMA BRCA1/2 V1.2 PS1 is for the same pathogenic missense substitution or a precisely matching pathogenic splice event; it does not apply to this frameshift.
Evidence considered
  • The case normalization identifies NM_007294.4:c.4331del as a frameshift, p.(Asn1444IlefsTer12), also written p.(N1444Ifs*12).
  • ENIGMA PS1 applies to predicted missense substitutions with the same amino-acid change, or to variants with the same predicted splicing event; neither mechanism applies here.
  • The requested variant notations were searched in all four governing full-text VCEP files and no variant-specific entry was found.
Still missing
  • No variant-specific entry was found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt.
  • No variant-specific entry was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No variant-specific entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No variant-specific entry was found in Appendices_V1.2_2024-11-18.docx.txt.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18vcep_specifications_table4_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18
PS2 VCEPNot applicable: ENIGMA v1.2 prohibits PS2 because de novo occurrences are not calibrated for relatively common BRCA1/2-related cancers. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1/2 VCEP specification v1.2 explicitly states that PS2 is not to be used because BRCA1/2-related cancers occur relatively commonly and the predictive capacity of de novo occurrences has not been calibrated. This governs regardless of whether parental testing or paternity confirmation is available. Searches of Specifications_V1.2_2024-11-18.docx.txt and HUMU-40-1557-s001.xlsx.txt found no entry for c.4331del, p.Asn1444IlefsTer12, or p.N1444Ifs*12.

VCEP rule
ENIGMA BRCA1/2 VCEP v1.2: PS2 is not to be used because de novo occurrences are not calibrated for BRCA1/2-related cancers.
Evidence considered
  • ENIGMA BRCA1/2 VCEP specification v1.2 states under PS2: do not use; BRCA1/2-related cancers occur relatively commonly and there is no information to calibrate the predictive capacity of de novo occurrences.
  • The case evidence bundle contains no proband-specific de novo or parental-testing evidence that could override the VCEP prohibition.
Still missing
  • No entry for c.4331del, p.Asn1444IlefsTer12, or p.N1444Ifs*12 was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No entry for c.4331del, p.Asn1444IlefsTer12, or p.N1444Ifs*12 was found in HUMU-40-1557-s001.xlsx.txt.
Sources
cspec ↗
PM1 VCEPNot applicable: residue 1444 is outside BRCA1 RING 2-101, coiled-coil 1391-1424, and BRCT 1650-1857 domains. Details ▾Hide ▴
Reasoning

PM1 is not applicable. The authoritative vcep_materials.json domain_tables object is empty for BRCA1, so there is no gene-specific domain-table entry to apply. The governing ENIGMA domain list nevertheless defines BRCA1 critical or potentially critical regions as RING aa 2-101, coiled-coil aa 1391-1424, and BRCT aa 1650-1857. The variant affects residue 1444 before the predicted termination at 1455: residue 1444 lies outside all three approved regions, and the variant is a frameshift rather than a missense variant in a mutational hotspot or critical domain. ENIGMA Table 1 also specifies that PM1 is not used for BRCA1/2 and is considered only as part of bioinformatic analysis for eligible missense or in-frame variants.

VCEP rule
ENIGMA BRCA1/2 V1.2: PM1 do not use; approved BRCA1 domains are RING 2-101, coiled-coil 1391-1424, and BRCT 1650-1857.
Evidence considered
  • vcep_materials.json has domain_tables as an empty object, so no separate gene-specific domain-table entry exists for BRCA1.
  • ENIGMA Appendix C and the specification define BRCA1 RING aa 2-101, coiled-coil aa 1391-1424, and BRCT aa 1650-1857 as the approved clinically important or potentially clinically important domains.
  • The variant's frameshift begins at Asn1444 and predicts termination at residue 1455, placing the initiating residue outside every listed domain.
  • ENIGMA Table 1 states PM1 is not used and is considered as part of bioinformatic analysis rather than assigned as a standalone domain code.
Still missing
  • No variant-specific entry was found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt.
  • No variant-specific entry was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No variant-specific entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No variant-specific entry was found in Appendices_V1.2_2024-11-18.docx.txt.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18
PM2 N/ANot applicable: ENIGMA excludes PM2 for deletion variants, even though c.4331del was absent from the specified non-cancer gnomAD datasets. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1 VCEP specifies PM2 Supporting for absence from an outbred population in gnomAD v2.1 non-cancer exomes and gnomAD v3.1 non-cancer genomes, with average regional read depth at least 25, but explicitly states not to apply PM2 Supporting to insertion, deletion, or delins variants. NM_007294.4:c.4331del is a one-base deletion, so PM2 is not applicable despite the recorded absence from both specified non-cancer datasets.

Rule
PM2 Supporting requires absence from gnomAD v2.1 non-cancer exomes and gnomAD v3.1 non-cancer genomes with regional average read depth >=25, but do not apply for insertion, deletion, or delins variants.
Evidence considered
  • ENIGMA BRCA1 VCEP PM2 rule: apply Supporting evidence for absence from controls in gnomAD v2.1 non-cancer exomes and gnomAD v3.1 non-cancer genomes when regional average read depth is at least 25.
  • The same VCEP specification explicitly states that PM2 Supporting must not be applied to insertion, deletion, or delins variants; c.4331del is a deletion.
  • The case evidence records absence from gnomAD v2.1 non-cancer and gnomAD v3.1 non-cancer, but that absence cannot overcome the VCEP deletion exclusion.
Still missing
  • No exact c.4331del, p.Asn1444IlefsTer12, or p.N1444Ifs*12 entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No exact c.4331del, p.Asn1444IlefsTer12, or p.N1444Ifs*12 entry was found in Appendices_V1.2_2024-11-18.docx.txt.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗
PM4 VCEPNot applicable: ENIGMA does not use PM4, which is reserved for in-frame length changes or stop-loss variants, not this frameshift PTC. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1/2 specification explicitly states that PM4 is not used and is considered as a component of bioinformatic analysis. PM4 is defined for protein-length changes from in-frame deletions/insertions in non-repeat regions or stop-loss variants, whereas this variant is a frameshift with a premature termination codon; therefore PM4 is not applicable.

VCEP rule
ENIGMA BRCA1/2 Specification v1.2: PM4 is not used; the criterion is not applicable to a frameshift PTC.
Evidence considered
  • Specifications_V1.2_2024-11-18.docx.txt Table 1 defines PM4 as protein-length changes from in-frame deletions/insertions in a non-repeat region or stop-loss variants and specifies Do not use.
  • The case normalization identifies c.4331del as a frameshift producing p.(Asn1444IlefsTer12), not an in-frame indel or stop-loss variant.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
PM6 VCEPNot applicable: ENIGMA v1.2 prohibits PM6 because assumed de novo occurrences are not calibrated for relatively common BRCA1/2-related cancers. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1/2 VCEP specification v1.2 explicitly states that PM6 is not to be used because BRCA1/2-related cancers occur relatively commonly and the predictive capacity of de novo occurrences has not been calibrated. This governs assumed de novo observations without confirmed paternity and maternity. Searches of Specifications_V1.2_2024-11-18.docx.txt and HUMU-40-1557-s001.xlsx.txt found no entry for c.4331del, p.Asn1444IlefsTer12, or p.N1444Ifs*12.

VCEP rule
ENIGMA BRCA1/2 VCEP v1.2: PM6 is not to be used because assumed de novo occurrences are not calibrated for BRCA1/2-related cancers.
Evidence considered
  • ENIGMA BRCA1/2 VCEP specification v1.2 states under PM6: do not use; BRCA1/2-related cancers occur relatively commonly and there is no information to calibrate the predictive capacity of de novo occurrences.
  • The case evidence bundle contains no proband-specific assumed-de-novo or parental-testing evidence that could override the VCEP prohibition.
Still missing
  • No entry for c.4331del, p.Asn1444IlefsTer12, or p.N1444Ifs*12 was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No entry for c.4331del, p.Asn1444IlefsTer12, or p.N1444Ifs*12 was found in HUMU-40-1557-s001.xlsx.txt.
Sources
cspec ↗
PP2 VCEPNot applicable: PP2 is restricted to missense variants, whereas c.4331del is a frameshift producing p.(Asn1444IlefsTer12). Details ▾Hide ▴
Reasoning

PP2 is not applicable because the variant is a frameshift, not a missense variant. The ENIGMA BRCA1/2 specification explicitly marks PP2 as do not use because of the high frequency of benign missense variants, and its rule is limited to missense variation in a gene where missense is a common disease mechanism. No codon-level or missense-mechanism PP2 evidence can be assigned to c.4331del.

VCEP rule
ENIGMA BRCA1/2 V1.2 PP2 is a missense-only criterion and is marked do not use.
Evidence considered
  • The case consequence is frameshift, not missense.
  • ENIGMA Table 1 lists PP2 as do not use because of the high frequency of benign missense variants.
Still missing
  • No variant-specific entry was found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt.
  • No variant-specific entry was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No variant-specific entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No variant-specific entry was found in Appendices_V1.2_2024-11-18.docx.txt.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
PP3 N/ANot applicable: c.4331del is a frameshift, outside ENIGMA PP3 scope, so the available SpliceAI max delta 0.007 is not evaluated. Details ▾Hide ▴
Reasoning

Not applicable by consequence scope. NM_007294.4:c.4331del is a frameshift producing NP_009225.1:p.(Asn1444IlefsTer12), not a missense, in-frame, synonymous, intronic, or splice-region variant eligible for the ENIGMA BRCA1 PP3 computational pathway. The ENIGMA specification limits PP3 to protein-impact prediction for missense/in-frame variants or splice-impact prediction for silent, missense/in-frame, and eligible intronic variants; therefore SpliceAI max delta 0.007 is not evaluated for PP3. No variant-specific entry was found when SupplementaryTables_V1.2_2024-11-18.xlsx.txt, Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, and PMID_22505045_Houdayer_2012_HumMutat.pdf.txt were searched for c.4331del, p.Asn1444IlefsTer12, and p.N1444Ifs*12.

Rule
ENIGMA BRCA1/2 v1.2 PP3 scope: missense/in-frame protein-impact prediction or eligible splice-impact prediction; frameshift variants are not applicable.
Evidence considered
  • Case normalization identifies NM_007294.4:c.4331del as a frameshift producing NP_009225.1:p.(Asn1444IlefsTer12), which is outside the ENIGMA PP3 computational criterion scope.
  • ENIGMA BRCA1/2 Specification v1.2 states that PP3 applies to missense or in-frame variants via protein-impact prediction and to specified silent, missense/in-frame, or intronic variants via SpliceAI; it does not apply to frameshifts.
  • The case evidence reports SpliceAI max delta 0.007, but this score was not used because the frameshift consequence is outside PP3 scope.
Still missing
  • No variant-specific entry found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt for c.4331del, p.Asn1444IlefsTer12, or p.N1444Ifs*12; this is not an evidence gap because PP3 is out of scope for a frameshift.
  • No variant-specific entry found in Specifications_V1.2_2024-11-18.docx.txt for c.4331del, p.Asn1444IlefsTer12, or p.N1444Ifs*12; this is not an evidence gap because PP3 is out of scope for a frameshift.
  • No variant-specific entry found in Appendices_V1.2_2024-11-18.docx.txt for c.4331del, p.Asn1444IlefsTer12, or p.N1444Ifs*12; this is not an evidence gap because PP3 is out of scope for a frameshift.
  • No variant-specific entry found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt for c.4331del, p.Asn1444IlefsTer12, or p.N1444Ifs*12; this is not an evidence gap because PP3 is out of scope for a frameshift.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18
BP1 N/ANot applicable: BP1 covers silent, missense, or in-frame changes, not the c.4331del frameshift despite SpliceAI max delta 0.007. Details ▾Hide ▴
Reasoning

BP1 is not applicable because c.4331del is a frameshift, whereas the ENIGMA BP1_Strong rule applies to silent, missense, or in-frame insertion/deletion/delins variants outside an approved functional domain with no predicted splicing impact. The variant's SpliceAI max delta is 0.007, but that does not convert a frameshift into an eligible BP1 variant type. The predicted frameshift begins at residue 1444, outside the listed BRCA1 coiled-coil domain boundary of 1391-1424, but variant type remains dispositive.

Rule
ENIGMA BRCA1/2 V1.2 BP1_Strong requires a silent, missense, or in-frame insertion/deletion/delins variant outside a potentially clinically important domain and SpliceAI <=0.1.
Evidence considered
  • The case consequence is frameshift p.(Asn1444IlefsTer12), not silent, missense, or in-frame insertion/deletion/delins.
  • The case bundle reports SpliceAI max delta 0.007, below the ENIGMA no-splicing threshold of 0.1, but BP1 still fails the required variant-type gate.
  • The initiating residue 1444 is outside the ENIGMA coiled-coil domain at aa 1391-1424.
Still missing
  • No variant-specific entry was found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt.
  • No variant-specific entry was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No variant-specific entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No variant-specific entry was found in Appendices_V1.2_2024-11-18.docx.txt.
Sources
cspec ↗spliceai ↗vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18
BP2 VCEPNot applicable: the ENIGMA BRCA1/2 specification says BP2 is not used and permits it only as part of BS2, not as an independent criterion. Details ▾Hide ▴
Reasoning

The governing ENIGMA BRCA1/2 specification explicitly states that BP2 is not used for BRCA1/2 classification and is applied only in the context of BS2. It therefore does not permit BP2 to be assigned independently for an observation in trans with a pathogenic variant in this fully penetrant dominant disorder or in cis with a pathogenic variant in any inheritance pattern. The Specifications_V1.2_2024-11-18.docx was searched for c.4331del, p.Asn1444IlefsTer12, and p.N1444Ifs*12; no variant-specific BP2 entry was found, consistent with the criterion-level rule that BP2 is not applicable.

VCEP rule
ENIGMA BP2: Do not use; applied only in the context of BS2.
Evidence considered
  • ENIGMA BRCA1/2 Specifications v1.2, Table 1: BP2 is marked Do not use and is applied only in the context of BS2.
  • Specifications_V1.2_2024-11-18.docx was searched for c.4331del, p.Asn1444IlefsTer12, and p.N1444Ifs*12; no variant-specific BP2 entry was found.
Still missing
  • No variant-specific BP2 entry was found in Specifications_V1.2_2024-11-18.docx after searching c.4331del, p.Asn1444IlefsTer12, and p.N1444Ifs*12; the governing rule itself makes BP2 not applicable.
Sources
cspec ↗
BP3 VCEPNot applicable: ENIGMA does not use BP3, which is reserved for in-frame indels in functionless repeat regions, not this frameshift PTC. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1/2 specification explicitly states that BP3 is not used and is captured by bioinformatic tool prediction and domain analysis. BP3 is defined for in-frame deletions/insertions in a repetitive region without a known function, whereas this variant is a frameshift producing a premature termination codon; therefore BP3 is not applicable.

VCEP rule
ENIGMA BRCA1/2 Specification v1.2: BP3 is not used; the criterion is not applicable to a frameshift PTC.
Evidence considered
  • Specifications_V1.2_2024-11-18.docx.txt Table 1 defines BP3 as in-frame deletions/insertions in a repetitive region without a known function and specifies Do not use.
  • The case normalization identifies c.4331del as a frameshift producing p.(Asn1444IlefsTer12), not an in-frame deletion or insertion.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
BP4 N/ANot applicable: c.4331del is a frameshift, outside ENIGMA BP4 scope, so the available SpliceAI max delta 0.007 is not evaluated. Details ▾Hide ▴
Reasoning

Not applicable by consequence scope. NM_007294.4:c.4331del is a frameshift producing NP_009225.1:p.(Asn1444IlefsTer12), not a missense, in-frame, synonymous, intronic, or splice-region variant eligible for the ENIGMA BRCA1 BP4 computational pathway. The ENIGMA specification limits BP4 to protein-impact and/or splice-impact assessment for specified non-truncating variant types and eligible intronic variants; therefore SpliceAI max delta 0.007 is not evaluated for BP4. No variant-specific entry was found when SupplementaryTables_V1.2_2024-11-18.xlsx.txt, Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, and PMID_22505045_Houdayer_2012_HumMutat.pdf.txt were searched for c.4331del, p.Asn1444IlefsTer12, and p.N1444Ifs*12.

Rule
ENIGMA BRCA1/2 v1.2 BP4 scope: specified non-truncating or eligible intronic variants with no predicted protein/splice impact; frameshift variants are not applicable.
Evidence considered
  • Case normalization identifies NM_007294.4:c.4331del as a frameshift producing NP_009225.1:p.(Asn1444IlefsTer12), which is outside the ENIGMA BP4 computational criterion scope.
  • ENIGMA BRCA1/2 Specification v1.2 states that BP4 applies to specified missense/in-frame, silent, or eligible intronic variants with no predicted protein or splice impact; it does not apply to frameshifts.
  • The case evidence reports SpliceAI max delta 0.007, but this score was not used because the frameshift consequence is outside BP4 scope.
Still missing
  • No variant-specific entry found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt for c.4331del, p.Asn1444IlefsTer12, or p.N1444Ifs*12; this is not an evidence gap because BP4 is out of scope for a frameshift.
  • No variant-specific entry found in Specifications_V1.2_2024-11-18.docx.txt for c.4331del, p.Asn1444IlefsTer12, or p.N1444Ifs*12; this is not an evidence gap because BP4 is out of scope for a frameshift.
  • No variant-specific entry found in Appendices_V1.2_2024-11-18.docx.txt for c.4331del, p.Asn1444IlefsTer12, or p.N1444Ifs*12; this is not an evidence gap because BP4 is out of scope for a frameshift.
  • No variant-specific entry found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt for c.4331del, p.Asn1444IlefsTer12, or p.N1444Ifs*12; this is not an evidence gap because BP4 is out of scope for a frameshift.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18
BP7 N/ANot applicable: c.4331del is a frameshift, not a synonymous or eligible intronic variant, so BP7 and SpliceAI max delta 0.007 are not evaluated. Details ▾Hide ▴
Reasoning

Not applicable by consequence scope. NM_007294.4:c.4331del is a frameshift producing NP_009225.1:p.(Asn1444IlefsTer12), not a synonymous variant or an eligible intronic variant. The ENIGMA specification limits BP7 to silent variants or qualifying intronic variants when BP4 is met; therefore SpliceAI max delta 0.007 is not evaluated for BP7. No variant-specific entry was found when SupplementaryTables_V1.2_2024-11-18.xlsx.txt, Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, and PMID_22505045_Houdayer_2012_HumMutat.pdf.txt were searched for c.4331del, p.Asn1444IlefsTer12, and p.N1444Ifs*12.

Rule
ENIGMA BRCA1/2 v1.2 BP7 scope: synonymous or qualifying intronic variants only; frameshift variants are not applicable.
Evidence considered
  • Case normalization identifies NM_007294.4:c.4331del as a frameshift producing NP_009225.1:p.(Asn1444IlefsTer12), which is outside the ENIGMA BP7 criterion scope.
  • ENIGMA BRCA1/2 Specification v1.2 states that BP7 applies to silent variants, and to qualifying intronic variants when BP4 is met; it does not apply to frameshifts.
  • The case evidence reports SpliceAI max delta 0.007, but this score was not used because the frameshift consequence is outside BP7 scope.
Still missing
  • No variant-specific entry found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt for c.4331del, p.Asn1444IlefsTer12, or p.N1444Ifs*12; this is not an evidence gap because BP7 is out of scope for a frameshift.
  • No variant-specific entry found in Specifications_V1.2_2024-11-18.docx.txt for c.4331del, p.Asn1444IlefsTer12, or p.N1444Ifs*12; this is not an evidence gap because BP7 is out of scope for a frameshift.
  • No variant-specific entry found in Appendices_V1.2_2024-11-18.docx.txt for c.4331del, p.Asn1444IlefsTer12, or p.N1444Ifs*12; this is not an evidence gap because BP7 is out of scope for a frameshift.
  • No variant-specific entry found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt for c.4331del, p.Asn1444IlefsTer12, or p.N1444Ifs*12; this is not an evidence gap because BP7 is out of scope for a frameshift.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18

Identifiers

Gene
BRCA1
Transcript
NM_007294.4
Coding (HGVS c.)
NM_007294.4:c.4331del
Protein (HGVS p.)
NP_009225.1:p.(Asn1444IlefsTer12)
GRCh38
chr17:43082429 AT>A
GRCh37
chr17:41234446 AT>A
Location and type
Exon 12 · frameshift

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 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +11 bp
0.000
SpliceAI acceptor gainat +143 bp
0.007
SpliceAI donor lossat -27 bp
0.000
SpliceAI donor gainat -25 bp
0.002
Pangolin splice lossmagnitude shown
-0.051
Pangolin splice gain
0.011

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 N/ANot applicable: c.4331del is a frameshift, outside ENIGMA PP3 scope, so the available SpliceAI max delta 0.007 is not evaluated. Details ▾Hide ▴
Reasoning

Not applicable by consequence scope. NM_007294.4:c.4331del is a frameshift producing NP_009225.1:p.(Asn1444IlefsTer12), not a missense, in-frame, synonymous, intronic, or splice-region variant eligible for the ENIGMA BRCA1 PP3 computational pathway. The ENIGMA specification limits PP3 to protein-impact prediction for missense/in-frame variants or splice-impact prediction for silent, missense/in-frame, and eligible intronic variants; therefore SpliceAI max delta 0.007 is not evaluated for PP3. No variant-specific entry was found when SupplementaryTables_V1.2_2024-11-18.xlsx.txt, Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, and PMID_22505045_Houdayer_2012_HumMutat.pdf.txt were searched for c.4331del, p.Asn1444IlefsTer12, and p.N1444Ifs*12.

Rule
ENIGMA BRCA1/2 v1.2 PP3 scope: missense/in-frame protein-impact prediction or eligible splice-impact prediction; frameshift variants are not applicable.
Evidence considered
  • Case normalization identifies NM_007294.4:c.4331del as a frameshift producing NP_009225.1:p.(Asn1444IlefsTer12), which is outside the ENIGMA PP3 computational criterion scope.
  • ENIGMA BRCA1/2 Specification v1.2 states that PP3 applies to missense or in-frame variants via protein-impact prediction and to specified silent, missense/in-frame, or intronic variants via SpliceAI; it does not apply to frameshifts.
  • The case evidence reports SpliceAI max delta 0.007, but this score was not used because the frameshift consequence is outside PP3 scope.
Still missing
  • No variant-specific entry found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt for c.4331del, p.Asn1444IlefsTer12, or p.N1444Ifs*12; this is not an evidence gap because PP3 is out of scope for a frameshift.
  • No variant-specific entry found in Specifications_V1.2_2024-11-18.docx.txt for c.4331del, p.Asn1444IlefsTer12, or p.N1444Ifs*12; this is not an evidence gap because PP3 is out of scope for a frameshift.
  • No variant-specific entry found in Appendices_V1.2_2024-11-18.docx.txt for c.4331del, p.Asn1444IlefsTer12, or p.N1444Ifs*12; this is not an evidence gap because PP3 is out of scope for a frameshift.
  • No variant-specific entry found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt for c.4331del, p.Asn1444IlefsTer12, or p.N1444Ifs*12; this is not an evidence gap because PP3 is out of scope for a frameshift.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18
BP4 N/ANot applicable: c.4331del is a frameshift, outside ENIGMA BP4 scope, so the available SpliceAI max delta 0.007 is not evaluated. Details ▾Hide ▴
Reasoning

Not applicable by consequence scope. NM_007294.4:c.4331del is a frameshift producing NP_009225.1:p.(Asn1444IlefsTer12), not a missense, in-frame, synonymous, intronic, or splice-region variant eligible for the ENIGMA BRCA1 BP4 computational pathway. The ENIGMA specification limits BP4 to protein-impact and/or splice-impact assessment for specified non-truncating variant types and eligible intronic variants; therefore SpliceAI max delta 0.007 is not evaluated for BP4. No variant-specific entry was found when SupplementaryTables_V1.2_2024-11-18.xlsx.txt, Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, and PMID_22505045_Houdayer_2012_HumMutat.pdf.txt were searched for c.4331del, p.Asn1444IlefsTer12, and p.N1444Ifs*12.

Rule
ENIGMA BRCA1/2 v1.2 BP4 scope: specified non-truncating or eligible intronic variants with no predicted protein/splice impact; frameshift variants are not applicable.
Evidence considered
  • Case normalization identifies NM_007294.4:c.4331del as a frameshift producing NP_009225.1:p.(Asn1444IlefsTer12), which is outside the ENIGMA BP4 computational criterion scope.
  • ENIGMA BRCA1/2 Specification v1.2 states that BP4 applies to specified missense/in-frame, silent, or eligible intronic variants with no predicted protein or splice impact; it does not apply to frameshifts.
  • The case evidence reports SpliceAI max delta 0.007, but this score was not used because the frameshift consequence is outside BP4 scope.
Still missing
  • No variant-specific entry found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt for c.4331del, p.Asn1444IlefsTer12, or p.N1444Ifs*12; this is not an evidence gap because BP4 is out of scope for a frameshift.
  • No variant-specific entry found in Specifications_V1.2_2024-11-18.docx.txt for c.4331del, p.Asn1444IlefsTer12, or p.N1444Ifs*12; this is not an evidence gap because BP4 is out of scope for a frameshift.
  • No variant-specific entry found in Appendices_V1.2_2024-11-18.docx.txt for c.4331del, p.Asn1444IlefsTer12, or p.N1444Ifs*12; this is not an evidence gap because BP4 is out of scope for a frameshift.
  • No variant-specific entry found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt for c.4331del, p.Asn1444IlefsTer12, or p.N1444Ifs*12; this is not an evidence gap because BP4 is out of scope for a frameshift.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18
BP7 N/ANot applicable: c.4331del is a frameshift, not a synonymous or eligible intronic variant, so BP7 and SpliceAI max delta 0.007 are not evaluated. Details ▾Hide ▴
Reasoning

Not applicable by consequence scope. NM_007294.4:c.4331del is a frameshift producing NP_009225.1:p.(Asn1444IlefsTer12), not a synonymous variant or an eligible intronic variant. The ENIGMA specification limits BP7 to silent variants or qualifying intronic variants when BP4 is met; therefore SpliceAI max delta 0.007 is not evaluated for BP7. No variant-specific entry was found when SupplementaryTables_V1.2_2024-11-18.xlsx.txt, Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, and PMID_22505045_Houdayer_2012_HumMutat.pdf.txt were searched for c.4331del, p.Asn1444IlefsTer12, and p.N1444Ifs*12.

Rule
ENIGMA BRCA1/2 v1.2 BP7 scope: synonymous or qualifying intronic variants only; frameshift variants are not applicable.
Evidence considered
  • Case normalization identifies NM_007294.4:c.4331del as a frameshift producing NP_009225.1:p.(Asn1444IlefsTer12), which is outside the ENIGMA BP7 criterion scope.
  • ENIGMA BRCA1/2 Specification v1.2 states that BP7 applies to silent variants, and to qualifying intronic variants when BP4 is met; it does not apply to frameshifts.
  • The case evidence reports SpliceAI max delta 0.007, but this score was not used because the frameshift consequence is outside BP7 scope.
Still missing
  • No variant-specific entry found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt for c.4331del, p.Asn1444IlefsTer12, or p.N1444Ifs*12; this is not an evidence gap because BP7 is out of scope for a frameshift.
  • No variant-specific entry found in Specifications_V1.2_2024-11-18.docx.txt for c.4331del, p.Asn1444IlefsTer12, or p.N1444Ifs*12; this is not an evidence gap because BP7 is out of scope for a frameshift.
  • No variant-specific entry found in Appendices_V1.2_2024-11-18.docx.txt for c.4331del, p.Asn1444IlefsTer12, or p.N1444Ifs*12; this is not an evidence gap because BP7 is out of scope for a frameshift.
  • No variant-specific entry found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt for c.4331del, p.Asn1444IlefsTer12, or p.N1444Ifs*12; this is not an evidence gap because BP7 is out of scope for a frameshift.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).

4 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

  • Tumorigenesis in mice carrying a truncating Brca1 mutation.
    No paper-specific finding is recorded.
    PMID 11358863 ↗
  • The cancer connection: BRCA1 and BRCA2 tumor suppression in mice and humans.
    No paper-specific finding is recorded.
    PMID 12483515 ↗
  • Roles of BRCA1 and BRCA2 in homologous recombination, DNA replication fidelity and the cellular response to ionizing radiation.
    No paper-specific finding is recorded.
    PMID 12947386 ↗
  • BRCA1 16 years later: risk-associated BRCA1 mutations and their functional implications.
    No paper-specific finding is recorded.
    PMID 20608970 ↗

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

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.007 Open source ↗
ClinVar Captured ClinVar source record 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

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

ClinVar

This variant is absent from ClinVar.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).

Functional

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

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.