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BRCA2c.10043delUncertain significance
Print report
Variant interpretation report

BRCA2 c.10043del, p.Asn3348IlefsTer35

NM_000059.4:c.10043del NP_000050.3:p.(Asn3348IlefsTer35) Frameshift · exon 27 View identifiers
Classification
Uncertain significance

Variant description:

The BRCA2 NM_000059.4:c.10043del (NP_000050.3:p.(Asn3348IlefsTer35)) frameshift variant has not previously been reported in somatic cancers (COSMIC). Based on available guidelines, this variant is considered to be a Variant of Uncertain Significance (VUS).

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 BRCA2

BRCA2 encodes a DNA repair protein that maintains genome stability by repairing double-strand breaks through homologous recombination and by protecting DNA replication forks. It acts as a tumor suppressor, and inherited loss-of-function changes cause hereditary breast and ovarian cancer syndrome, with elevated lifetime risks of breast, ovarian, prostate, and pancreatic cancers; biallelic changes cause Fanconi anemia complementation group D1. Reduced or altered BRCA2 activity is implicated in multiple tumor types, and PARP inhibitors are an approved treatment for BRCA2-associated ovarian and breast cancers.

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 BRCA2 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 is met or applied, so the ENIGMA BRCA2 Table 3 pathogenic and benign combination rules are not satisfied.

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
0.205 maximum delta

Recorded SpliceAI maximum delta score: 0.205. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
No screenshot for this evidence
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 BRCA2 VCEP v1.2, with the data and sources behind each one.

28 criteria with recorded statuses: 0 met · 2 not met · 9 not assessed · 17 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 computational criteria are not applicable because NM_000059.4:c.10043del is a frameshift and the ENIGMA BRCA2 PP3, BP4, and BP7 paths do not cover frameshift variants.

The variant was searched under c.10043del, p.Asn3348IlefsTer35, and p.N3348Ifs*35 in all four on-record VCEP full-text files; no variant-level entry was found.

Not met · 2 · evaluated, threshold not reached

BA1 VCEPNot met: the variant was absent from gnomAD non-cancer searches, so its maximum filter allele frequency was not above the BA1 threshold of 0.001. Details ▾Hide ▴
Reasoning

The variant is absent from the available gnomAD v2.1 and v4.1 records, including the governing non-cancer population searches. Therefore, the ENIGMA BA1 threshold of maximum filter allele frequency above 0.001 is not reached. The variant is a deletion, but BA1 has no deletion exclusion; the applicable read-depth and founder-variant caveats cannot create a positive frequency finding when the variant is absent.

VCEP rule
Apply based on maximum filter allele frequency observed in a gnomAD non-founder population, considering exome and genome data separately. ... 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).
Evidence considered
  • gnomAD v2.1 record for GRCh37 13-32972690-TA-T: search_status absent; source data empty.
  • gnomAD v4.1 record for GRCh38 chr13-32398553-TA-T: search_status absent; source data empty.
  • The case evidence separately reports the variant absent from GNOMAD_V2_1_NON_CANCER and GNOMAD_V3_1_NON_CANCER.
  • ENIGMA Appendix G states that BA1 uses the highest filter allele frequency in a non-founder gnomAD population, assessing exome and genome separately.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗vcep_appendices_v1_2_2024_11_18 ↗
BS1 VCEPNot met: no gnomAD non-cancer allele was observed, so the maximum filter allele frequency did not exceed the BS1 threshold of 0.0001. Details ▾Hide ▴
Reasoning

The variant is absent from the available gnomAD v2.1 and v4.1 records, including the governing non-cancer population searches. Thus no filter allele frequency exceeds 0.0001, so neither BS1 Strong nor BS1 Supporting can be assigned. The variant is a deletion, but the VCEP does not exclude deletions from BS1; absence simply does not meet a frequency-above-threshold criterion.

VCEP rule
Apply based on maximum filter allele frequency in a gnomAD non-founder population, considering exome and genome data separately. ... 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). ... 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).
Evidence considered
  • gnomAD v2.1 record for GRCh37 13-32972690-TA-T: search_status absent; source data empty.
  • gnomAD v4.1 record for GRCh38 chr13-32398553-TA-T: search_status absent; source data empty.
  • The case evidence separately reports the variant absent from GNOMAD_V2_1_NON_CANCER and GNOMAD_V3_1_NON_CANCER.
  • ENIGMA Appendix G gives BS1 as filter allele frequency greater than 0.0001 and recommends assessing the highest filter allele frequency in non-founder gnomAD populations separately by exome and genome.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗vcep_appendices_v1_2_2024_11_18 ↗

Not assessed · 9 · no assessment recorded

PS3 VCEPNot assessed: no variant-specific calibrated functional assay or ENIGMA Table 9 entry was found for c.10043del/p.Asn3348IlefsTer35. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 v1.2 functional rule requires well-established functional studies supportive of a damaging effect, with protein-only or combined mRNA/protein assays evaluated through Figure 1C and calibrated recommendations in Table 9. Searches of Specifications_Table9_V1.2_2024-11-18.xlsx, SupplementaryTables_V1.2_2024-11-18.xlsx, HUMU-40-1557-s001.xlsx, Specifications_V1.2_2024-11-18.docx, and Appendices_V1.2_2024-11-18.docx found no entry for c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35. The reviewed functional publications also did not test or report this variant; their assays concerned other BRCA2 truncations or general BRCA2 biology. Therefore no variant-specific calibrated functional result is available to apply PS3.

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 Specifications Table 9 search: no row for c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35.
  • ENIGMA Supplementary Tables search: no row for c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35.
  • Parsons et al. multifactorial supplementary data search: no functional-assay row for c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35.
  • ENIGMA Specifications v1.2 and Appendices v1.2: PS3 functional-assay pathway requires well-established damaging functional evidence and directs calibrated published assay results to Table 9; no variant-specific result was present.
Still missing
  • No entry for c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35 in Specifications_Table9_V1.2_2024-11-18.xlsx.
  • No entry for c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35 in SupplementaryTables_V1.2_2024-11-18.xlsx.
  • No entry for c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35 in HUMU-40-1557-s001.xlsx.
  • No variant-specific PS3 assay rule or result for this variant in Specifications_V1.2_2024-11-18.docx.
  • No variant-specific PS3 assay result for this variant in Appendices_V1.2_2024-11-18.docx.
  • The reviewed functional papers PMID:10570174, PMID:11239455, PMID:20878484, PMID:22193408, and PMID:24312913 did not report a functional assay of this variant.
Sources
cspec ↗vcep_specifications_table9_v1_2_2024_11_18 ↗vcep_specifications_v1_2_2024_11_18 ↗PMID:10570174 ↗PMID:11239455 ↗PMID:20878484 ↗PMID:22193408 ↗PMID:24312913 ↗
PS4 VCEPNot assessed: no variant-specific case-control counts, odds ratio, p-value, or confidence interval were available to evaluate the ENIGMA PS4 thresholds. Details ▾Hide ▴
Reasoning

The ENIGMA rule requires a matched case-control study with p-value ≤0.05, OR ≥4, and a lower confidence interval excluding 2.0. No variant-level entry was found for c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35 in SupplementaryTables_V1.2_2024-11-18.xlsx.txt or HUMU-40-1557-s001.xlsx.txt. The literature_pass.json ai_classified_papers list is empty, and the five reviewed full-text papers in paper_extracts.json do not report this variant in an affected-patient/control comparison. Therefore PS4 cannot be evaluated from the available case-control evidence; no OR or confidence interval can be calculated.

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).
Evidence considered
  • Specifications_V1.2_2024-11-18.docx, PS4: "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)."
  • SupplementaryTables_V1.2_2024-11-18.xlsx.txt was searched for c.10043del, p.Asn3348IlefsTer35, and p.N3348Ifs*35; no matching row was found.
  • HUMU-40-1557-s001.xlsx.txt was searched for c.10043del, p.Asn3348IlefsTer35, and p.N3348Ifs*35; no matching row was found.
  • The literature packet's ai_classified_papers list is empty. The five extracted full-text papers were checked and each states that the variant is not mentioned; none supplies affected-case/control counts for this variant.
Still missing
  • No entry found after searching SupplementaryTables_V1.2_2024-11-18.xlsx.txt for c.10043del, p.Asn3348IlefsTer35, and p.N3348Ifs*35.
  • No entry found after searching HUMU-40-1557-s001.xlsx.txt for c.10043del, p.Asn3348IlefsTer35, and p.N3348Ifs*35.
  • No variant-specific case-control data were reported in the five literature papers represented in paper_extracts.json: PMID:10570174, PMID:11239455, PMID:20878484, PMID:22193408, and PMID:24312913.
  • The ENIGMA PS4 thresholds cannot be tested without variant-specific case/control counts or a reported OR with p-value and confidence interval.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_supplementarytables_v1_2_2024_11_18 ↗vcep_humu_40_1557_s001 ↗PMID:10570174 ↗PMID:11239455 ↗PMID:20878484 ↗PMID:22193408 ↗PMID:24312913 ↗
PM3 VCEPNot assessed: no Fanconi Anemia proband, co-occurrent pathogenic BRCA2 variant, or phase evidence is documented for the variant. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 VCEP limits PM3 to a patient with a phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia and a co-occurrent variant in the same gene. The available case evidence identifies NM_000059.4:c.10043del / p.(Asn3348IlefsTer35) but provides no affected-proband observation with Fanconi Anemia phenotype, chromosome-breakage result, second pathogenic or likely pathogenic BRCA2 variant, or phase evidence. Therefore the PM3 point total cannot be determined and PM3 is not assessed.

VCEP rule
Apply for patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia (FA), and co-occurrent variants in the same gene. ... 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, PM3 rule: PM3 applies for a patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia (FA) and co-occurrent variants in the same gene; Table 6 assigns points per proband and the final PM3 code is based on the summed points.
  • The case evidence bundle identifies the variant as NM_000059.4:c.10043del, NP_000050.3:p.(Asn3348IlefsTer35), and NP_000050.3:p.(N3348Ifs*35), but reports no proband-level Fanconi Anemia phenotype, co-occurrent BRCA2 pathogenic/likely pathogenic variant, or phase information.
Still missing
  • No entry for c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35 was found in Specifications_V1.2_2024-11-18.docx.txt.
  • The case evidence bundle contains no affected-proband Fanconi Anemia phenotype, chromosome-breakage result, co-occurrent pathogenic or likely pathogenic BRCA2 variant, or phase assignment for this variant.
Sources
vcep_specifications_v1_2_2024_11_18 ↗cspec ↗
PP1 VCEPNot assessed: no variant-specific co-segregation LR or pedigree data are available to compare with the VCEP PP1 supporting threshold of LR >=2.08:1. Details ▾Hide ▴
Reasoning

The VCEP requires quantitative co-segregation evidence and assigns PP1 strength by likelihood ratio: supporting at LR >=2.08:1, moderate at LR >=4.3:1, strong at LR >=18.7:1, and very strong at LR >=350:1. The case materials contain no variant-specific pedigree, parental testing, meioses, affected-relative segregation data, or quantitative co-segregation LR for NM_000059.4:c.10043del. The three governing VCEP files were searched under c.10043del, p.Asn3348IlefsTer35, and p.N3348Ifs*35 with no matching row: SupplementaryTables_V1.2_2024-11-18.xlsx, Specifications_V1.2_2024-11-18.docx, and HUMU-40-1557-s001.xlsx.

VCEP rule
Co-segregation with disease in multiple affected family members See Appendix I Apply weight as per Bayes Score: PP1 - LR ≥2.08:1 PP1_Moderate – LR≥4.3:1 PP1_Strong – LR≥18.7:1 PP1_Very Strong – LR≥350:1
Evidence considered
  • ENIGMA BRCA2 Specifications v1.2, Table 1, PP1_VariableWeight: quantitative co-segregation is required and PP1 is assigned by Bayes-score LR thresholds; no variant-specific LR or segregation observations are present in the case evidence.
  • The three on-record governing VCEP full-text files were searched for c.10043del, p.Asn3348IlefsTer35, and p.N3348Ifs*35; none contained a matching variant row.
Still missing
  • No variant-specific quantitative co-segregation likelihood ratio, pedigree, affected-relative genotype data, parental testing, or meioses were available.
  • No entry for c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35 was found in SupplementaryTables_V1.2_2024-11-18.xlsx (full-text conversion searched).
  • No entry for c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35 was found in Specifications_V1.2_2024-11-18.docx (full-text conversion searched).
  • No entry for c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35 was found in HUMU-40-1557-s001.xlsx (full-text conversion searched).
Sources
cspec ↗
PP4 VCEPNot assessed: no variant-specific combined clinical likelihood ratio was available to compare with the ENIGMA PP4 threshold of LR ≥2.08. Details ▾Hide ▴
Reasoning

The ENIGMA rule permits PP4 only for combined, clinically calibrated likelihood evidence toward pathogenicity. The governing thresholds are LR ≥2.08 for Supporting, ≥4.3 for Moderate, ≥18.7 for Strong, and ≥350 for Very Strong. No matching BRCA2 c.10043del row was found in PMID_31853058_BRCA2_clinical_history_LR.xlsx.txt, and the available paper extracts contain no variant-specific clinical-history, pathology, co-occurrence, segregation, or case-control likelihood data. Consequently, no combined LR is available for comparison with the PP4 thresholds.

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
Evidence considered
  • Specifications_V1.2_2024-11-18.docx, PP4: "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."
  • PMID_31853058_BRCA2_clinical_history_LR.xlsx.txt was searched for c.10043del, p.Asn3348IlefsTer35, and p.N3348Ifs*35; no matching row was found.
  • The available extracts for Li et al. 2020, Easton et al. 2007, and Parsons et al. 2019 contain methodology or other-variant information but no variant-specific combined LR for this variant.
Still missing
  • No BRCA2 c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35 row found in PMID_31853058_BRCA2_clinical_history_LR.xlsx.txt.
  • No variant-specific combined clinical LR was reported in the available literature extracts.
  • A clinical-history, pathology, co-occurrence, segregation, or case-control LR component set is needed to calculate the combined LR.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_pmid_31853058_brca2_clinical_history_lr ↗PMID:31853058 ↗PMID:17924331 ↗PMID:31131967 ↗
BS2 VCEPNot assessed: no eligible healthy-adult homozygote, heterozygote, or trans co-occurrence observation with the required phenotype and age context was available. Details ▾Hide ▴
Reasoning

The available evidence contains no variant-specific observation in a healthy adult, no homozygote count, and no documented co-occurrence in trans with a pathogenic or likely pathogenic BRCA2 variant in a phenotyped clinical or research cohort. The VCEP requires the Table 8 point-based approach for such observations; without an eligible observation and the required age, cancer, phase, and Fanconi-anemia context, BS2 cannot be evaluated.

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. ... BS2 = ≥ 4 points
Evidence considered
  • The available case evidence contains gnomAD absence results but no homozygote count or individual-level healthy-adult phenotype observation for this variant.
  • ENIGMA Appendix H Table 13 requires eligible phenotyped clinical or research cohort observations and assigns points according to trans co-occurrence or homozygosity plus age/cancer follow-up context.
  • ENIGMA Appendix H explicitly states that gnomAD homozygote frequency observations are not to be used for the BS2 point scheme and are instead captured by BA1 or BS1 when applicable.
Still missing
  • No variant-specific healthy-adult observation, homozygote observation, or trans co-occurrence with a pathogenic/likely pathogenic BRCA2 variant was available.
  • No Table 8 point-assignment data for age at cancer onset or cancer-unaffected follow-up and Fanconi-anemia assessment was available.
Sources
cspec ↗vcep_appendices_v1_2_2024_11_18 ↗
BS3 VCEPNot assessed: no variant-specific calibrated functional assay or ENIGMA Table 9 entry was found for c.10043del/p.Asn3348IlefsTer35. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 v1.2 functional rule requires well-established functional studies showing no damaging effect on protein function, with protein-only or combined mRNA/protein assays evaluated through Figure 1C and calibrated recommendations in Table 9. Searches of Specifications_Table9_V1.2_2024-11-18.xlsx, SupplementaryTables_V1.2_2024-11-18.xlsx, HUMU-40-1557-s001.xlsx, Specifications_V1.2_2024-11-18.docx, and Appendices_V1.2_2024-11-18.docx found no entry for c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35. The reviewed functional publications also did not test or report this variant; their assays concerned other BRCA2 variants or general BRCA2 biology. Therefore no variant-specific calibrated functional result is available to apply BS3.

VCEP rule
Well-established in vitro or in vivo functional studies shows no damaging effect on protein function. Apply BS3 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 Specifications Table 9 search: no row for c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35.
  • ENIGMA Supplementary Tables search: no row for c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35.
  • Parsons et al. multifactorial supplementary data search: no functional-assay row for c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35.
  • ENIGMA Specifications v1.2 and Appendices v1.2: BS3 functional-assay pathway requires well-established evidence showing no damaging effect on protein function and directs calibrated published assay results to Table 9; no variant-specific result was present.
Still missing
  • No entry for c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35 in Specifications_Table9_V1.2_2024-11-18.xlsx.
  • No entry for c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35 in SupplementaryTables_V1.2_2024-11-18.xlsx.
  • No entry for c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35 in HUMU-40-1557-s001.xlsx.
  • No variant-specific BS3 assay rule or result for this variant in Specifications_V1.2_2024-11-18.docx.
  • No variant-specific BS3 assay result for this variant in Appendices_V1.2_2024-11-18.docx.
  • The reviewed functional papers PMID:10570174, PMID:11239455, PMID:20878484, PMID:22193408, and PMID:24312913 did not report a functional assay of this variant.
Sources
cspec ↗vcep_specifications_table9_v1_2_2024_11_18 ↗vcep_specifications_v1_2_2024_11_18 ↗PMID:10570174 ↗PMID:11239455 ↗PMID:20878484 ↗PMID:22193408 ↗PMID:24312913 ↗
BS4 VCEPNot assessed: no variant-specific non-segregation LR or affected-family data are available to compare with the VCEP BS4 supporting threshold of LR <=0.48 to >0.23:1. Details ▾Hide ▴
Reasoning

The VCEP requires quantitative co-segregation evidence showing lack of segregation and assigns BS4 strength by likelihood ratio: supporting at LR <=0.48 to >0.23:1, moderate at LR <=0.23:1, strong at LR <=0.05:1, and very strong at LR <=0.00285:1. The case materials contain no variant-specific non-segregation observations, pedigree, parental testing, affected-relative genotype data, meioses, or quantitative co-segregation LR for NM_000059.4:c.10043del. The three governing VCEP files were searched under c.10043del, p.Asn3348IlefsTer35, and p.N3348Ifs*35 with no matching row: SupplementaryTables_V1.2_2024-11-18.xlsx, Specifications_V1.2_2024-11-18.docx, and HUMU-40-1557-s001.xlsx.

VCEP rule
Lack of segregation in affected members of a family. See Appendix I. Apply weight as per Bayes Score: BS4_Supporting - LR ≤0.48 to &gt;0.23:1 BS4_Moderate - LR ≤0.23:1 BS4 - LR ≤0.05:1 BS4_Very strong – LR ≤0.00285:1
Evidence considered
  • ENIGMA BRCA2 Specifications v1.2, Table 1, BS4_VariableWeight: quantitative co-segregation analysis is required for lack of segregation and BS4 is assigned by Bayes-score LR thresholds; no variant-specific LR or non-segregation observations are present in the case evidence.
  • The three on-record governing VCEP full-text files were searched for c.10043del, p.Asn3348IlefsTer35, and p.N3348Ifs*35; none contained a matching variant row.
Still missing
  • No variant-specific quantitative non-segregation likelihood ratio, pedigree, affected-relative genotype data, parental testing, or meioses were available.
  • No entry for c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35 was found in SupplementaryTables_V1.2_2024-11-18.xlsx (full-text conversion searched).
  • No entry for c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35 was found in Specifications_V1.2_2024-11-18.docx (full-text conversion searched).
  • No entry for c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35 was found in HUMU-40-1557-s001.xlsx (full-text conversion searched).
Sources
cspec ↗
BP5 VCEPNot assessed: no variant-specific combined clinical likelihood ratio was available to test the ENIGMA BP5 Supporting inequality LR ≤0.48. Details ▾Hide ▴
Reasoning

The ENIGMA rule restricts BP5 to combined, clinically calibrated likelihood evidence against pathogenicity, with Supporting requiring LR ≤0.48, Moderate LR ≤0.23, Strong LR ≤0.05, or Very Strong LR ≤0.00285. No matching variant row was found in PMID_31853058_BRCA2_clinical_history_LR.xlsx.txt, and no variant-specific combined clinical LR or alternate molecular-basis evidence was available in the reviewed extracts. The required inequality therefore cannot be evaluated.

VCEP rule
Use ONLY to capture combined LR against pathogenicity, based on multifactorial likelihood clinical data. BP5 - LR ≤0.48 to >0.23:1
Evidence considered
  • Specifications_V1.2_2024-11-18.docx, BP5: "Use ONLY to capture combined LR against pathogenicity, based on multifactorial likelihood clinical data. BP5_VeryStrong – LR ≤0.00285:1; BP5_Strong - LR ≤0.05:1; BP5_Moderate - LR ≤0.23:1; BP5 - LR ≤0.48 to >0.23:1."
  • Explicit threshold check required by the VCEP rule: LR ≤0.48? cannot be evaluated because no variant-specific LR is available.
  • PMID_31853058_BRCA2_clinical_history_LR.xlsx.txt was searched for all three variant notations; no matching row was found.
Still missing
  • No BRCA2 c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35 row found in PMID_31853058_BRCA2_clinical_history_LR.xlsx.txt.
  • No variant-specific combined LR against pathogenicity was reported in the available literature extracts.
  • A clinically calibrated alternate-molecular-basis or multifactorial LR dataset is needed to evaluate BP5.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_pmid_31853058_brca2_clinical_history_lr ↗PMID:31853058 ↗PMID:17924331 ↗PMID:31131967 ↗
Not applicable · 17· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANot applicable: ENIGMA Table 4 assigns PVS1_N/A to BRCA2 exon 27 PTCs terminating after p.E3309, and this frameshift terminates at p.3382. Details ▾Hide ▴
Reasoning

NM_000059.4:c.10043del is a BRCA2 frameshift, NP_000050.3:p.(Asn3348IlefsTer35), in exon 27 of the governing NM_000059.4 transcript. The predicted termination is at p.3382, after the exon-27 Table 4 boundary p.E3309; the pre-assigned ENIGMA Table 4 row therefore specifies PVS1_N/A for PTC>p.E3309. This governing exon-specific decision controls over a generic loss-of-function or NMD assessment.

VCEP rule
Null variant in a gene where loss of function is a known mechanism of disease. ... For predicted protein termination codon (PTC) variants, apply with exon-specific weights derived for the PM5 (PTC) code (see description below). ... PVS1_N/A PTC>p.E3309 PM5_N/A
Evidence considered
  • Case consequence: NM_000059.4:c.10043del is a frameshift producing NP_000050.3:p.(Asn3348IlefsTer35), also written p.(N3348Ifs*35), with the affected variant assigned to exon 27.
  • ENIGMA BRCA2 Specifications Table 4, exon 27 row: PVS1 applies to PTC<p.T3310, whereas PVS1_N/A applies to PTC>p.E3309; this variant terminates at p.3382 and therefore follows the PVS1_N/A row.
  • The exact variant notation was searched in Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, Specifications_Table4_V1.2_2024-11-18.xlsx.txt, and PMID_22505045_Houdayer_2012_HumMutat.pdf.txt; no exact notation was found in those files, apart from the applicable exon-level rule row in Table 4.
Still missing
  • No exact c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35 notation was found in Specifications_V1.2_2024-11-18.docx.txt; the exon-27 governing row was found.
  • No exact c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35 notation was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No exact c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35 notation was found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt; the applicable exon-27 PVS1_N/A row was found.
  • No exact c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35 notation was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_specifications_table4_v1_2_2024_11_18 ↗
PS1 N/ANot applicable: the variant is a frameshift, while ENIGMA PS1 applies to missense substitutions or matched splicing events, not this consequence. Details ▾Hide ▴
Reasoning

PS1 is not applicable because NM_000059.4:c.10043del is a frameshift producing p.(Asn3348IlefsTer35), whereas the ENIGMA PS1 protein-change route is limited to predicted missense substitutions and its alternative route is for variants with the same predicted splicing impact as a previously classified (likely) pathogenic variant. The governing VCEP files were searched for c.10043del, p.Asn3348IlefsTer35, and p.N3348Ifs*35; no exact variant entry was found in Specifications_V1.2_2024-11-18.docx, Appendices_V1.2_2024-11-18.docx, Specifications_Table4_V1.2_2024-11-18.xlsx, or SupplementaryTables_V1.2_2024-11-18.xlsx. SpliceAI max delta is 0.205, but this does not convert the frameshift into a qualifying same-splicing-event comparator under the PS1 rule.

VCEP rule
Apply PS1, for predicted missense substitutions, where a previously classified pathogenic variant is considered to act via protein change (no confirmed or predicted effect on mRNA splicing (SpliceAI≤0.1)). ... Apply PS1_Variable Weight, for exonic and intronic variants with same predicted impact on splicing, as a previously classified (likely) pathogenic variant.
Evidence considered
  • Variant facts: NM_000059.4:c.10043del is a frameshift with predicted protein consequence NP_000050.3:p.(Asn3348IlefsTer35) / p.(N3348Ifs*35).
  • ENIGMA Specifications v1.2, PS1 rule: the protein-change route applies to predicted missense substitutions; the splicing route requires the same predicted impact on splicing as a previously classified (likely) pathogenic variant.
  • SpliceAI result: maximum delta score 0.205; no qualifying previously classified comparator with the same predicted splicing event was identified.
  • Direct searches of the four governing BRCA2 full-text files for c.10043del, p.Asn3348IlefsTer35, and p.N3348Ifs*35 found no exact variant entry.
Still missing
  • No exact c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35 entry found in Specifications_V1.2_2024-11-18.docx.
  • No exact c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35 entry found in Appendices_V1.2_2024-11-18.docx.
  • No exact c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35 entry found in Specifications_Table4_V1.2_2024-11-18.xlsx.
  • No exact c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35 entry found in SupplementaryTables_V1.2_2024-11-18.xlsx.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗spliceai ↗
PS2 VCEPNot applicable: the ENIGMA BRCA2 VCEP explicitly prohibits PS2 because de novo occurrences lack calibrated predictive capacity for relatively common BRCA1/2-related cancers. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 VCEP explicitly says not to use PS2 because BRCA1/2-related cancers occur relatively commonly and there is no information to calibrate the predictive capacity of de novo occurrences.

VCEP rule
De novo (paternity confirmed) in a patient with the disease and no family history. ... Do not use ... BRCA1/2-related cancers occur relatively commonly. No information to calibrate the predictive capacity of de novo occurrences.
Evidence considered
  • ENIGMA BRCA2 Specifications v1.2, Table 1, PS2: the criterion is marked "Do not use" and gives the reason that BRCA1/2-related cancers occur relatively commonly with no calibration of de novo predictive capacity.
Sources
cspec ↗
PM1 VCEPNot applicable: ENIGMA explicitly says PM1 should not be used for BRCA2, regardless of functional-domain location. Details ▾Hide ▴
Reasoning

PM1 is not applicable under the BRCA2 ENIGMA VCEP specification: the criterion is explicitly marked 'Do not use' and is considered only as a component of PP3/BP4. The case's vcep_materials.json contains no domain_tables entry; independently, the VCEP text defines the BRCA2 PALB2-binding domain as aa 10-40 and DNA-binding domain as aa 2481-3186, neither of which provides a PM1 route for this frameshift under the explicit prohibition.

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, Table 1 PM1 entry: 'Do not use'; PM1 is considered as a component of bioinformatic analysis (PP3/BP4).
  • ENIGMA domain definition: BRCA2 PALB2 binding domain aa 10-40 and BRCA2 DNA binding aa 2481-3186; the case vcep_materials.json domain_tables object is empty.
  • Direct searches of the four governing BRCA2 full-text files for c.10043del, p.Asn3348IlefsTer35, and p.N3348Ifs*35 found no exact variant entry.
Still missing
  • No exact c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35 entry found in Specifications_V1.2_2024-11-18.docx.
  • No exact c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35 entry found in Appendices_V1.2_2024-11-18.docx.
  • No exact c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35 entry found in Specifications_Table4_V1.2_2024-11-18.xlsx.
  • No exact c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35 entry found in SupplementaryTables_V1.2_2024-11-18.xlsx.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗
PM2 N/ANot applicable: ENIGMA excludes deletion variants from PM2, and NM_000059.4:c.10043del is a deletion. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 specification explicitly excludes insertion, deletion, and delins variants from PM2. This variant is NM_000059.4:c.10043del, a one-base deletion, so PM2 is not applicable regardless of its absence from the gnomAD v2.1 and v3.1 non-cancer datasets or any unavailable read-depth value.

VCEP rule
Observation of a variant only once in a gnomAD outbred population is not informative. Do not apply for insertion, deletion or delins variants. Do not apply if read depth <25 at region around the variant.
Evidence considered
  • Variant Validator identifies NM_000059.4:c.10043del as a deletion and predicts NP_000050.3:p.(N3348Ifs*35).
  • The case evidence reports the variant absent from GNOMAD_V2_1_NON_CANCER and GNOMAD_V3_1_NON_CANCER, but this does not override the VCEP deletion exclusion.
  • ENIGMA Appendix G states that PM2_Supporting is not recommended for insertion, deletion, or insertion-deletion variants because of low recall estimates for these variant types.
Sources
cspec ↗vcep_appendices_v1_2_2024_11_18 ↗gnomad_v2 ↗gnomad_v4 ↗
PM4 VCEPNot applicable: ENIGMA says not to use PM4, which is limited to in-frame length changes or stop-loss variants, unlike this frameshift PTC. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 specification explicitly says not to use PM4 and limits it to protein length changes from in-frame deletions/insertions in a non-repeat region or stop-loss variants. This variant is a frameshift with a premature termination codon, not an in-frame deletion/insertion or stop-loss variant, so PM4 is not applicable.

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
  • ENIGMA BRCA2 Specifications Table 1, PM4: protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants; the specification says Do not use and considers PM4 part of bioinformatic analysis (PP3/BP4).
  • Case consequence is a frameshift PTC, p.(Asn3348IlefsTer35), not an in-frame deletion/insertion or stop-loss variant.
  • The exact variant notation was searched in all four governing files named for this assessment and was not found.
Still missing
  • No exact c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35 notation was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No exact c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35 notation was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No exact c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35 notation was found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt.
  • No exact c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35 notation was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗
PM5 N/ANot applicable: exon 27 PTC variants after p.E3309 receive PM5_N/A in ENIGMA Table 4, and this variant terminates at p.Ter3382. Details ▾Hide ▴
Reasoning

Classic missense PM5 is not applicable to this frameshift. ENIGMA repurposes PM5 for genomic protein-termination-codon variants annotated as PVS1, with strength determined by exon and Table 4. The variant is in BRCA2 exon 27 and produces a termination codon after p.E3309; the governing Table 4 row assigns PVS1_N/A and PM5_N/A for exon 27 PTC variants >p.E3309. Therefore the pre-assigned PM5_N/A code governs, and no PM5 evidence is applied.

VCEP rule
Protein termination codon (PTC) variant in an exon where a different proven pathogenic PTC variant has been seen before. Use to justify additional weight for PTC variants annotated as PVS1. Only applied to genomic PTC changes (not splicing). Weight determined by exon where the nucleotide change occurs.
Evidence considered
  • Variant facts: NM_000059.4:c.10043del is a frameshift in BRCA2 exon 27 with predicted protein consequence p.(Asn3348IlefsTer35), placing the termination codon after p.E3309 (p.Ter3382).
  • ENIGMA Specifications v1.2, PM5 (PTC) rule: PM5 is repurposed for a genomic PTC in an exon where a different proven pathogenic PTC has been seen, as additional weight for a PVS1-annotated PTC; Table 4 determines exon-specific strength.
  • Specifications Table 4, BRCA2 E27 row: 'PVS1_N/A | PTC>p.E3309 | PM5_N/A'. This pre-assigned code governs the variant's PM5 assessment.
  • Direct searches of the four governing BRCA2 full-text files for c.10043del, p.Asn3348IlefsTer35, and p.N3348Ifs*35 found no exact variant entry.
Still missing
  • No exact c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35 entry found in Specifications_V1.2_2024-11-18.docx.
  • No exact c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35 entry found in Appendices_V1.2_2024-11-18.docx.
  • No exact c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35 entry found in Specifications_Table4_V1.2_2024-11-18.xlsx; the exon-keyed governing row was used instead.
  • No exact c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35 entry found in SupplementaryTables_V1.2_2024-11-18.xlsx.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_specifications_table4_v1_2_2024_11_18 ↗
PM6 VCEPNot applicable: the ENIGMA BRCA2 VCEP explicitly prohibits PM6 because de novo occurrences lack calibrated predictive capacity for relatively common BRCA1/2-related cancers. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 VCEP explicitly says not to use PM6 because BRCA1/2-related cancers occur relatively commonly and there is no information to calibrate the predictive capacity of de novo occurrences.

VCEP rule
Confirmed de novo without confirmation of paternity and maternity. ... Do not use ... BRCA1/2-related cancers occur relatively commonly. No information to calibrate the predictive capacity of de novo occurrences.
Evidence considered
  • ENIGMA BRCA2 Specifications v1.2, Table 1, PM6: the criterion is marked "Do not use" and gives the reason that BRCA1/2-related cancers occur relatively commonly with no calibration of de novo predictive capacity.
Sources
cspec ↗
PP2 VCEPNot applicable: ENIGMA says PP2 should not be used, and this variant is a frameshift rather than a missense change. Details ▾Hide ▴
Reasoning

PP2 is explicitly marked 'Do not use' by the BRCA2 ENIGMA VCEP. In addition, this variant is a frameshift rather than a missense variant, so it does not fall within the criterion's stated variant type.

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
Evidence considered
  • ENIGMA Specifications v1.2, Table 1 PP2 entry: 'Do not use'; the criterion's original description is limited to a missense variant.
  • Variant facts: NM_000059.4:c.10043del is a frameshift with predicted protein consequence p.(Asn3348IlefsTer35).
  • Direct searches of the four governing BRCA2 full-text files for c.10043del, p.Asn3348IlefsTer35, and p.N3348Ifs*35 found no exact variant entry.
Still missing
  • No exact c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35 entry found in Specifications_V1.2_2024-11-18.docx.
  • No exact c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35 entry found in Appendices_V1.2_2024-11-18.docx.
  • No exact c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35 entry found in Specifications_Table4_V1.2_2024-11-18.xlsx.
  • No exact c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35 entry found in SupplementaryTables_V1.2_2024-11-18.xlsx.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗
PP3 N/ANot applicable: the frameshift is outside ENIGMA PP3 scope, which names missense, in-frame, silent, and qualifying intronic variants, despite SpliceAI 0.205. Details ▾Hide ▴
Reasoning

The variant is a frameshift, NM_000059.4:c.10043del, producing NP_000050.3:p.(Asn3348IlefsTer35). The ENIGMA BRCA2 PP3 rule covers missense or in-frame insertion, deletion or delins variants for protein-impact prediction, and silent, missense/in-frame, or qualifying intronic variants for SpliceAI-based prediction; frameshift variants are outside those PP3 paths. The rule also states not to apply PP3 if PVS1 is met at any strength. Therefore PP3 is not applicable, and the available SpliceAI max delta score of 0.205 is not used to extend PP3 to this frameshift.

VCEP rule
Do not apply PP3 if PVS1 is met at any strength. ... Apply PP3 for missense or in-frame insertion, deletion or delins variants inside a (potentially) clinically important functional domain and predicted impact via protein change (BayesDel predicted Impact). ... Apply PP3 for predicted splicing (SpliceAI ≥0.2) for silent, missense/in-frame (irrespective of location in clinically important functional domain) and for intronic variants outside of the donor and acceptor ±1,2 positions.
Evidence considered
  • ENIGMA BRCA2 Specifications v1.2, PP3 section: PP3 is limited to missense/in-frame protein-impact paths and predicted splicing for silent, missense/in-frame, or qualifying intronic variants; it also states not to apply PP3 if PVS1 is met at any strength.
  • Case variant assessment: NM_000059.4:c.10043del is a frameshift with protein consequence NP_000050.3:p.(Asn3348IlefsTer35), so it is outside the PP3 variant-type scope.
  • SpliceAI result for NM_000059.4:c.10043del: DS_AG 0.205, DS_AL 0.022, DS_DG 0.0, DS_DL 0.0, maximum delta score 0.205; this score is not used for PP3 because the variant type is outside the governing PP3 path.
Still missing
  • No variant-level entry found for c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35 in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No variant-level entry found for c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35 in Specifications_V1.2_2024-11-18.docx.txt.
  • No variant-level entry found for c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35 in Appendices_V1.2_2024-11-18.docx.txt.
  • No variant-level entry found for c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35 in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗pvs1_variant_assessmentspliceai ↗
PP5 VCEPNot applicable: the ENIGMA VCEP explicitly states that PP5 is not for use. Details ▾Hide ▴
Reasoning

The ENIGMA VCEP marks PP5 as not for use. No strength can be assigned under this VCEP-specific rule.

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
  • Specifications_V1.2_2024-11-18.docx, PP5: "Reputable source recently reports variant as pathogenic but the evidence is not available to the laboratory to perform an independent evaluation. Do not use."
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗
BP1 N/ANot applicable: BP1 excludes frameshifts and also requires SpliceAI ≤0.1, whereas this variant has a maximum delta of 0.205. Details ▾Hide ▴
Reasoning

BP1 is not applicable because the ENIGMA BP1 rule names silent substitutions, missense variants, and in-frame insertion/deletion/delins variants, whereas this is a frameshift. The rule also requires no predicted splicing (SpliceAI ≤0.1), while the case SpliceAI maximum delta is 0.205; both the variant-type gate and the splicing gate therefore fail. The VCEP-defined domains are BRCA2 PALB2 binding aa 10-40 and DNA binding aa 2481-3186, but domain assessment cannot make a frameshift eligible for BP1.

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 rule: BP1_Strong applies to silent substitution, missense, or in-frame insertion/deletion/delins variants outside a clinically important domain and requires no splicing predicted (SpliceAI ≤0.1).
  • Variant facts: NM_000059.4:c.10043del is a frameshift with predicted protein consequence p.(Asn3348IlefsTer35).
  • SpliceAI result: maximum delta score 0.205, above the VCEP BP1 cutoff of ≤0.1.
  • Direct searches of the four governing BRCA2 full-text files for c.10043del, p.Asn3348IlefsTer35, and p.N3348Ifs*35 found no exact variant entry.
Still missing
  • No exact c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35 entry found in Specifications_V1.2_2024-11-18.docx.
  • No exact c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35 entry found in Appendices_V1.2_2024-11-18.docx.
  • No exact c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35 entry found in Specifications_Table4_V1.2_2024-11-18.xlsx.
  • No exact c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35 entry found in SupplementaryTables_V1.2_2024-11-18.xlsx.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗spliceai ↗
BP2 VCEPNot applicable: the BRCA2 VCEP states BP2 is not to be used and limits it to the BS2 context. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 VCEP explicitly states that BP2 is not to be used and is applied only in the context of BS2. This criterion is therefore not applicable under the governing VCEP specification, regardless of whether phase or co-occurrence evidence 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, BP2 row: 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; the VCEP states 'Do not use' and 'Applied only in the context of BS2.'
Still missing
  • No entry for c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35 was found in Specifications_V1.2_2024-11-18.docx.txt.
Sources
vcep_specifications_v1_2_2024_11_18 ↗cspec ↗
BP3 VCEPNot applicable: ENIGMA says not to use BP3, which is limited to in-frame changes in functionless repeats, not this frameshift PTC. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 specification explicitly says not to use BP3 and defines it only for in-frame deletions/insertions in a repetitive region without a known function. This variant is a frameshift with a premature termination codon, so it does not meet BP3's named variant type or applicability.

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
  • ENIGMA BRCA2 Specifications Table 1, BP3: in-frame deletions/insertions in a repetitive region without a known function; the specification says Do not use and states it is captured by bioinformatic tool prediction and domain analysis.
  • Case consequence is a frameshift PTC, p.(Asn3348IlefsTer35), not an in-frame deletion or insertion in a repetitive region.
  • The exact variant notation was searched in all four governing files named for this assessment and was not found.
Still missing
  • No exact c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35 notation was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No exact c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35 notation was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No exact c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35 notation was found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt.
  • No exact c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35 notation was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗
BP4 N/ANot applicable: BP4 covers missense/in-frame, silent, or qualifying intronic variants, whereas this variant is a frameshift with SpliceAI maximum delta 0.205. Details ▾Hide ▴
Reasoning

The variant is a frameshift, not a missense, in-frame, silent, or intronic variant. The ENIGMA BRCA2 BP4 rule only provides paths for missense/in-frame variants, silent variants, and intronic variants outside donor and acceptor ±1,2 positions. BP4 is therefore not applicable to this frameshift; the SpliceAI max delta score of 0.205 does not create a BP4 path or negate the truncating protein consequence.

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). ... Silent variant inside a (potentially) clinically important functional domain, if no predicted impact via splicing (SpliceAI ≤0.1). ... Intronic variants outside of the donor and acceptor ±1,2 positions AND no predicted impact via splicing (SpliceAI ≤0.1).
Evidence considered
  • ENIGMA BRCA2 Specifications v1.2, BP4 section: BP4 applies only to missense/in-frame variants in the specified domain path, silent variants in the specified domain path, or qualifying intronic variants.
  • Case variant assessment: NM_000059.4:c.10043del is a frameshift producing NP_000050.3:p.(Asn3348IlefsTer35), which is outside all BP4 variant-type paths.
  • SpliceAI result: maximum delta score 0.205; this does not make BP4 applicable to a frameshift.
Still missing
  • No variant-level entry found for c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35 in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No variant-level entry found for c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35 in Specifications_V1.2_2024-11-18.docx.txt.
  • No variant-level entry found for c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35 in Appendices_V1.2_2024-11-18.docx.txt.
  • No variant-level entry found for c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35 in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗pvs1_variant_assessmentspliceai ↗
BP6 VCEPNot applicable: the ENIGMA VCEP explicitly states that BP6 is not for use. Details ▾Hide ▴
Reasoning

The ENIGMA VCEP marks BP6 as not for use. No strength can be assigned under this VCEP-specific rule.

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
  • Specifications_V1.2_2024-11-18.docx, BP6: "Reputable source recently reports variant as benign but the evidence is not available to the laboratory to perform an independent evaluation. Do not use."
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗
BP7 N/ANot applicable: BP7 requires a silent or qualifying intronic variant with BP4 met, but this variant is a frameshift and SpliceAI reaches 0.205. Details ▾Hide ▴
Reasoning

The variant is a frameshift, whereas the ENIGMA BRCA2 BP7 rule applies to silent variants inside a clinically important functional domain or intronic variants outside conserved donor or acceptor motif positions, and only if BP4 is met. Because this frameshift is outside the BP7 variant-type scope and BP4 is not applicable, BP7 is not applicable; the SpliceAI maximum delta score of 0.205 is not used to apply BP7.

VCEP rule
Apply BP7 for ... Silent variant inside a (potentially) clinically important functional domain, IF BP4 met. ... Intronic variants located outside conserved donor or acceptor motif positions (at or beyond positions +7/-21) IF BP4 met
Evidence considered
  • ENIGMA BRCA2 Specifications v1.2, BP7 section: BP7 applies to silent variants in the specified domain path or qualifying intronic variants, if BP4 is met.
  • Case variant assessment: NM_000059.4:c.10043del is a frameshift producing NP_000050.3:p.(Asn3348IlefsTer35), not a silent or intronic variant.
  • SpliceAI result: maximum delta score 0.205; BP7 cannot be applied because the variant is outside BP7 scope and BP4 is not met or applicable.
Still missing
  • No variant-level entry found for c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35 in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No variant-level entry found for c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35 in Specifications_V1.2_2024-11-18.docx.txt.
  • No variant-level entry found for c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35 in Appendices_V1.2_2024-11-18.docx.txt.
  • No variant-level entry found for c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35 in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗pvs1_variant_assessmentspliceai ↗

Identifiers

Gene
BRCA2
Transcript
NM_000059.4
Coding (HGVS c.)
NM_000059.4:c.10043del
Protein (HGVS p.)
NP_000050.3:p.(Asn3348IlefsTer35)
GRCh38
chr13:32398553 TA>T
GRCh37
chr13:32972690 TA>T
Location and type
Exon 27 · frameshift

Gene diagram

Every interpreted variant in BRCA2, mapped onto the exon structure of NM_000059.4. Select a row to find it on the plot.

BRCA2NM_000059.4
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 -415 bp
0.022
SpliceAI acceptor gainat +33 bp
0.205
SpliceAI donor lossat -376 bp
0.000
SpliceAI donor gainat +394 bp
0.000
Pangolin splice lossmagnitude shown
-0.049
Pangolin splice gain
0.126

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 N/ANot applicable: the frameshift is outside ENIGMA PP3 scope, which names missense, in-frame, silent, and qualifying intronic variants, despite SpliceAI 0.205. Details ▾Hide ▴
Reasoning

The variant is a frameshift, NM_000059.4:c.10043del, producing NP_000050.3:p.(Asn3348IlefsTer35). The ENIGMA BRCA2 PP3 rule covers missense or in-frame insertion, deletion or delins variants for protein-impact prediction, and silent, missense/in-frame, or qualifying intronic variants for SpliceAI-based prediction; frameshift variants are outside those PP3 paths. The rule also states not to apply PP3 if PVS1 is met at any strength. Therefore PP3 is not applicable, and the available SpliceAI max delta score of 0.205 is not used to extend PP3 to this frameshift.

VCEP rule
Do not apply PP3 if PVS1 is met at any strength. ... Apply PP3 for missense or in-frame insertion, deletion or delins variants inside a (potentially) clinically important functional domain and predicted impact via protein change (BayesDel predicted Impact). ... Apply PP3 for predicted splicing (SpliceAI ≥0.2) for silent, missense/in-frame (irrespective of location in clinically important functional domain) and for intronic variants outside of the donor and acceptor ±1,2 positions.
Evidence considered
  • ENIGMA BRCA2 Specifications v1.2, PP3 section: PP3 is limited to missense/in-frame protein-impact paths and predicted splicing for silent, missense/in-frame, or qualifying intronic variants; it also states not to apply PP3 if PVS1 is met at any strength.
  • Case variant assessment: NM_000059.4:c.10043del is a frameshift with protein consequence NP_000050.3:p.(Asn3348IlefsTer35), so it is outside the PP3 variant-type scope.
  • SpliceAI result for NM_000059.4:c.10043del: DS_AG 0.205, DS_AL 0.022, DS_DG 0.0, DS_DL 0.0, maximum delta score 0.205; this score is not used for PP3 because the variant type is outside the governing PP3 path.
Still missing
  • No variant-level entry found for c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35 in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No variant-level entry found for c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35 in Specifications_V1.2_2024-11-18.docx.txt.
  • No variant-level entry found for c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35 in Appendices_V1.2_2024-11-18.docx.txt.
  • No variant-level entry found for c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35 in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗pvs1_variant_assessmentspliceai ↗
BP4 N/ANot applicable: BP4 covers missense/in-frame, silent, or qualifying intronic variants, whereas this variant is a frameshift with SpliceAI maximum delta 0.205. Details ▾Hide ▴
Reasoning

The variant is a frameshift, not a missense, in-frame, silent, or intronic variant. The ENIGMA BRCA2 BP4 rule only provides paths for missense/in-frame variants, silent variants, and intronic variants outside donor and acceptor ±1,2 positions. BP4 is therefore not applicable to this frameshift; the SpliceAI max delta score of 0.205 does not create a BP4 path or negate the truncating protein consequence.

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). ... Silent variant inside a (potentially) clinically important functional domain, if no predicted impact via splicing (SpliceAI ≤0.1). ... Intronic variants outside of the donor and acceptor ±1,2 positions AND no predicted impact via splicing (SpliceAI ≤0.1).
Evidence considered
  • ENIGMA BRCA2 Specifications v1.2, BP4 section: BP4 applies only to missense/in-frame variants in the specified domain path, silent variants in the specified domain path, or qualifying intronic variants.
  • Case variant assessment: NM_000059.4:c.10043del is a frameshift producing NP_000050.3:p.(Asn3348IlefsTer35), which is outside all BP4 variant-type paths.
  • SpliceAI result: maximum delta score 0.205; this does not make BP4 applicable to a frameshift.
Still missing
  • No variant-level entry found for c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35 in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No variant-level entry found for c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35 in Specifications_V1.2_2024-11-18.docx.txt.
  • No variant-level entry found for c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35 in Appendices_V1.2_2024-11-18.docx.txt.
  • No variant-level entry found for c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35 in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗pvs1_variant_assessmentspliceai ↗
BP7 N/ANot applicable: BP7 requires a silent or qualifying intronic variant with BP4 met, but this variant is a frameshift and SpliceAI reaches 0.205. Details ▾Hide ▴
Reasoning

The variant is a frameshift, whereas the ENIGMA BRCA2 BP7 rule applies to silent variants inside a clinically important functional domain or intronic variants outside conserved donor or acceptor motif positions, and only if BP4 is met. Because this frameshift is outside the BP7 variant-type scope and BP4 is not applicable, BP7 is not applicable; the SpliceAI maximum delta score of 0.205 is not used to apply BP7.

VCEP rule
Apply BP7 for ... Silent variant inside a (potentially) clinically important functional domain, IF BP4 met. ... Intronic variants located outside conserved donor or acceptor motif positions (at or beyond positions +7/-21) IF BP4 met
Evidence considered
  • ENIGMA BRCA2 Specifications v1.2, BP7 section: BP7 applies to silent variants in the specified domain path or qualifying intronic variants, if BP4 is met.
  • Case variant assessment: NM_000059.4:c.10043del is a frameshift producing NP_000050.3:p.(Asn3348IlefsTer35), not a silent or intronic variant.
  • SpliceAI result: maximum delta score 0.205; BP7 cannot be applied because the variant is outside BP7 scope and BP4 is not met or applicable.
Still missing
  • No variant-level entry found for c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35 in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No variant-level entry found for c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35 in Specifications_V1.2_2024-11-18.docx.txt.
  • No variant-level entry found for c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35 in Appendices_V1.2_2024-11-18.docx.txt.
  • No variant-level entry found for c.10043del, p.Asn3348IlefsTer35, or p.N3348Ifs*35 in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗pvs1_variant_assessmentspliceai ↗

Statement

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 0.20).

5 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

  • Truncated BRCA2 is cytoplasmic: implications for cancer-linked mutations.
    The study examined BRCA2 nuclear localization signals and the cancer-associated 6174delT truncation, not c.10043del; it found truncation constructs lacking the relevant localization regions were predominantly cytoplasmic.
    Does not name this variant
    PMID 10570174 ↗
    Quoted passage
    In summary, within the final 156 amino acids of BRCA2 reside NLS1 and NLS3, the two functional NLSs of BRCA2. Each of these NLSs is downstream of all known cancer-associated truncating mutations, thereby giving rise to the hypothesis that these mutants cannot be functional because their products do not reach the nucleus.

    Results, ‘BRCA2 NLSs Reside in the Extreme C Terminus’; Results, ‘Endogenous Cancer-Associated BRCA2 Truncation Mutant Is Cytoplasmic’

  • BRCA2 is required for homology-directed repair of chromosomal breaks.
    The study measured homology-directed repair in cells carrying other BRCA2 lesions, including 6174delT and exon-27 deletions, not c.10043del; these other lesions impaired repair.
    Does not name this variant
    PMID 11239455 ↗
    Quoted passage
    The magnitude of the defect in the human CAPAN-1 cells is .100-fold as compared with other human cell lines, whereas in the Brca2lex1/lex2 cells, HDR is reduced 5- to 6-fold relative to wild-type ES cells.

    Discussion, first paragraph; Results sections on CAPAN-1 cells and Brca2 exon 27-deleted mouse ES cells

  • A new mutation of BRCA2 gene in an Italian healthy woman with familial breast cancer history.
    The study reported a different BRCA2 exon-15 insertion and its inferred truncation consequences, not c.10043del; no assay of the target variant was performed.
    Does not name this variant
    PMID 20878484 ↗
    Quoted passage
    The BRCA2 truncated protein loses many important domains, such as a portion of the DBD region that binds ssDNA, the C-terminal region, that contains the two putative nuclear localization signals (NLSs) and the extreme C-terminal region of BRCA2, that contains an additional Rad51-binding motif (Fig. 7).

    Results and Discussion, pp. 67–69; Conclusion, p. 70

  • BRCA1 and BRCA2: different roles in a common pathway of genome protection.
    This review summarizes BRCA2 loss-of-function biology and homologous recombination defects but does not report a variant-specific assay for c.10043del.
    Does not name this variant
    PMID 22193408 ↗
    Quoted passage
    BRCA2-deficient cells are defective in recruiting RAD51 to sites of DSBs and in repairing DSBs by HR

    Section: ‘BRCA2, HR and replication fidelity’

  • A comprehensive focus on global spectrum of BRCA1 and BRCA2 mutations in breast cancer.
    This review discusses general BRCA2 truncating mutations and critical C-terminal regions but does not report a variant-specific assay for c.10043del.
    Does not name this variant
    PMID 24312913 ↗
    Quoted passage
    In BRCA2 gene, most of mutations occur in exons 10 and 11 and usually include insertions or deletions which raise the missense alterations and premature stop codon ending in truncated and nonfunctional protein.

    Section 3, ‘BRCA1 and BRCA2 Mutations’

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 0.205 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 possible splice impact for this variant (max delta score = 0.20).

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.