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BRCA2c.8394_8396delinsAAPathogenic
Print report
Variant interpretation report

BRCA2 c.8394_8396delinsAA, p.Arg2799AsnfsTer22

NM_000059.4:c.8394_8396delinsAA NP_000050.3:p.(Arg2799AsnfsTer22) Frameshift · exon 19 View identifiers
Classification
Pathogenic

Variant description:

The BRCA2 NM_000059.4:c.8394_8396delinsAA (NP_000050.3:p.(Arg2799AsnfsTer22)) frameshift variant has not previously been reported in somatic cancers (COSMIC). This variant is predicted to result in an absent or disrupted protein product. Based on available guidelines, this variant is considered to be Pathogenic. This variant is considered to be Pathogenic by the VCEP (Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA); ClinVar ID 52573).

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 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: 3 Benign evidence criteria: 0
Pathogenic criteria applied · 3
PVS1Very strong
PVS1 · very strong

Met: ENIGMA Table 4 assigns full PVS1 to BRCA2 exon 19 PTC variants, and this variant is a frameshift producing p.Arg2799AsnfsTer22.

PM5Strong
PM5 · strong

Met, Strong: ENIGMA Table 4 preassigns PM5_Strong (PTC) for BRCA2 exon 19, where this genomic frameshift creates a termination codon.

PP5Supporting
PP5 · supporting

Not applicable: the ENIGMA BRCA2 specification explicitly states that PP5 is not to be used.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Pathogenic

Pathogenic: PVS1 (very strong) plus PM5 (strong) satisfy the ENIGMA BRCA2 VCEP Table 3 Pathogenic rule.

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

Absent from gnomAD-Canada v1.0.

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

Recorded SpliceAI maximum delta score: 0.130. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
ClinVar submissions
9 reported laboratory submissions

9 Pathogenic. ClinVar API review status: reviewed by expert panel.

Applied · PP5 → 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: 3 met · 2 not met · 9 not assessed · 14 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

PVS1 is met at very strong strength because the variant is a frameshift/PTC in BRCA2 exon 19 and ENIGMA Table 4 assigns PVS1 to exon 19 PTC variants.

PM4 and BP3 are not applicable because the ENIGMA BRCA2 VCEP explicitly says not to use either criterion.

All three computational criteria are not_applicable because the variant is a frameshift and lies outside the variant classes named by the ENIGMA PP3, BP4, and BP7 rules.

SpliceAI max delta 0.13 was not used to assign PP3, BP4, or BP7 because criterion applicability is determined first by the VCEP-defined variant scope.

Met · 3

PVS1 Very strongVCEPMet: ENIGMA Table 4 assigns full PVS1 to BRCA2 exon 19 PTC variants, and this variant is a frameshift producing p.Arg2799AsnfsTer22. Details ▾Hide ▴
Reasoning

NM_000059.4:c.8394_8396delinsAA is a frameshift producing NP_000050.3:p.(Arg2799AsnfsTer22) / p.(R2799Nfs*22) in exon 19. ENIGMA Table 4 assigns PVS1 to BRCA2 exon 19 PTC variants, and the VCEP rule directs exon-specific application for predicted PTC variants. The variant therefore meets full-strength PVS1 (very strong); no named VCEP downgrade applies to this exon 19 PTC entry. Exact searches for all three requested notations found no variant-specific row in the named full-text files, but the governing exon-level Table 4 assignment directly covers this frameshift/PTC consequence.

VCEP rule
Null variant in a gene where loss of function is a known mechanism of disease. ... In alignment with SVI recommendations for PVS1 code application, evidence strength and description has been separated for different variant types. Apply according to PVS1 flowchart, which considers knowledge of clinically important functional domains. For predicted protein termination codon (PTC) variants, apply with exon-specific weights derived for the PM5 (PTC) code (see description below). ... See Table 4, provided as a separate searchable excel file, for a comprehensive summary of codes applicable for all variants considered against the BRCA1 and BRCA2 PVS1 decision trees (initiation, nonsense/frameshift, deletion, duplication, splice site (donor/acceptor ±1,2)) – organized by exon.
Evidence considered
  • Variant facts: NM_000059.4:c.8394_8396delinsAA; frameshift; NP_000050.3:p.(Arg2799AsnfsTer22) / p.(R2799Nfs*22); exon 19.
  • ENIGMA Specifications Table 4, BRCA2 E19 PTC row: 'BRCA2 E19 ... PVS1 PTC PM5_Strong (PTC)'; the exon 19 section also lists the exon boundaries c.8332-c.8487 and protein interval p.2778-p.2829.
  • The VCEP specification states that PVS1 applies to a null variant in a gene where loss of function is a known mechanism of disease, is applied according to the PVS1 flowchart, and that predicted PTC variants use exon-specific weights.
  • The BRCA2 VCEP gene context marks loss of function as an established disease mechanism and the PVS1 gene gate as eligible.
Still missing
  • No exact c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22 entry was found in Specifications_V1.2_2024-11-18.docx.txt; its governing PVS1 rule was applied.
  • No exact c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22 entry was found in Appendices_V1.2_2024-11-18.docx.txt; the governing exon-level rule was applied.
  • No exact c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22 entry was found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt; the applicable BRCA2 exon 19 PTC row was present.
  • No exact c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22 entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt; this paper provided no variant-specific evidence for this coding frameshift.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_specifications_table4_v1_2_2024_11_18 ↗PMID:22505045 ↗
PM5 StrongVCEPMet, Strong: ENIGMA Table 4 preassigns PM5_Strong (PTC) for BRCA2 exon 19, where this genomic frameshift creates a termination codon. Details ▾Hide ▴
Reasoning

The variant is a genomic frameshift producing a protein termination codon in BRCA2 exon 19. The ENIGMA specification repurposes PM5 for PTC variants and requires a different proven pathogenic PTC variant in the same exon; Specifications Table 4 assigns PM5_Strong (PTC) to BRCA2 exon 19. This is the governing pre-assigned exon-level code, so PM5 is met at Strong strength. The exact variant notation itself was not found in the searched VCEP files, but the exon-level PM5 assignment is present and applies to this exon 19 frameshift.

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. See Specifications Table 4 for PM5_PTC code strengths applicable per exon. See Appendix D for additional details.
Evidence considered
  • Case facts: NM_000059.4:c.8394_8396delinsAA is a frameshift in BRCA2 exon 19 with predicted protein consequence p.(Arg2799AsnfsTer22).
  • Specifications_Table4_V1.2_2024-11-18.xlsx, BRCA2 E19 row: PVS1; PTC; PM5_Strong (PTC). This is the VCEP's pre-assigned code strength for protein-termination variants in exon 19.
  • Specifications_V1.2_2024-11-18.docx defines the repurposed PM5_VariableWeight (PTC) route for a PTC variant in an exon where a different proven pathogenic PTC variant has been seen before.
Still missing
  • No exact c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22 entry was found in Specifications_V1.2_2024-11-18.docx, Appendices_V1.2_2024-11-18.docx, SupplementaryTables_V1.2_2024-11-18.xlsx, or Specifications_Table4_V1.2_2024-11-18.xlsx; Table 4 supplies the governing exon-level PM5_Strong (PTC) assignment for BRCA2 E19.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_specifications_table4_v1_2_2024_11_18 ↗
PP5 SupportingVCEPNot applicable: the ENIGMA BRCA2 specification explicitly states that PP5 is not to be used. Details ▾Hide ▴
Reasoning

Expert panel Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) classified as Pathogenic.

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 row: reputable-source pathogenic reports are followed by the specification instruction Do not use.
  • ClinVar variation 52573 has an expert-panel Pathogenic classification, but the governing VCEP PP5 rule prohibits applying PP5.
  • ClinVar expert panel classification
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗clinvar ↗

Not met · 2 · evaluated, threshold not reached

BA1 VCEPNot met: the exact variant is absent from gnomAD v2.1 and v4.1, so no filter allele frequency exceeds the ENIGMA BA1 threshold of 0.001. Details ▾Hide ▴
Reasoning

BA1 is not met. The ENIGMA BRCA2 rule requires filter allele frequency above 0.1% (FAF > 0.001) in the specified non-founder gnomAD populations. The case evidence records the exact variant as absent from gnomAD v2.1 and gnomAD v4.1; no qualifying FAF above the BA1 threshold is available. The VCEP's preferred datasets are gnomAD v2.1 non-cancer exomes and gnomAD v3.1 non-cancer genomes, and the exact variant is also recorded as absent from the non-cancer v2.1 and v3.1 queries. The four governing VCEP full-text files were searched for c.8394_8396delinsAA, p.Arg2799AsnfsTer22, and p.R2799Nfs*22 with no exact variant entry found: 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 HUMU-40-1557-s001.xlsx.txt.

VCEP rule
Filter allele frequency (FAF) is above 0.1% (FAF > 0.001) in gnomAD v2.1 (non-cancer, exome only subset) and/or gnomAD v3.1 (non-cancer), non-founder population(s). See Appendix G for details.
Evidence considered
  • GNOMAD_V2_1: exact variant query 13-32944601-TAG-AA, search_status absent; evidence sentence: Absent from gnomAD v2.1.
  • GNOMAD_V4_1: exact variant query 13-32370464-TAG-AA, search_status absent; evidence sentence: Absent from gnomAD v4.1.
  • GNOMAD_V2_1_NON_CANCER: exact variant query 13-32944601-TAG-AA, search_status absent; evidence sentence: Absent from gnomAD v2.1 non-cancer.
  • GNOMAD_V3_1_NON_CANCER: exact variant query 13-32370464-TAG-AA, search_status absent; evidence sentence: Absent from gnomAD v3.1 non-cancer.
Still missing
  • No exact variant entry found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt for c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22.
  • No exact variant entry found in Specifications_V1.2_2024-11-18.docx.txt for c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22.
  • No exact variant entry found in Appendices_V1.2_2024-11-18.docx.txt for c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22.
  • No exact variant entry found in HUMU-40-1557-s001.xlsx.txt for c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗gnomad_v2 ↗gnomad_v4 ↗
BS1 VCEPNot met: the exact variant is absent from the relevant gnomAD datasets, providing no FAF above the ENIGMA BS1 Supporting threshold of 0.00002. Details ▾Hide ▴
Reasoning

BS1 is not met. The ENIGMA BRCA2 rule requires FAF above 0.01% for BS1 Strong or above 0.002% and at most 0.01% for BS1 Supporting in the specified non-founder gnomAD populations. The exact variant is absent from gnomAD v2.1 and v4.1, and from the non-cancer v2.1 and v3.1 queries, so no qualifying FAF is present. The four governing VCEP full-text files were searched for c.8394_8396delinsAA, p.Arg2799AsnfsTer22, and p.R2799Nfs*22 with no exact variant entry found: 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 HUMU-40-1557-s001.xlsx.txt.

VCEP rule
Filter allele frequency (FAF) is above 0.01% (FAF > 0.0001) in gnomAD v2.1 (non-cancer, exome only subset) and/or gnomAD v3.1 (non-cancer), non-founder population(s). See Appendix G for details. ... Filter allele frequency (FAF) is above 0.002% (FAF > 0.00002) and less than or equal to 0.01% (FAF ≤ 0.0001) in gnomAD v2.1 (non-cancer, exome only subset) and/or gnomAD v3.1 (non-cancer), non-founder population(s). See Appendix G for details.
Evidence considered
  • GNOMAD_V2_1: exact variant query 13-32944601-TAG-AA, search_status absent; evidence sentence: Absent from gnomAD v2.1.
  • GNOMAD_V4_1: exact variant query 13-32370464-TAG-AA, search_status absent; evidence sentence: Absent from gnomAD v4.1.
  • GNOMAD_V2_1_NON_CANCER: exact variant query 13-32944601-TAG-AA, search_status absent; evidence sentence: Absent from gnomAD v2.1 non-cancer.
  • GNOMAD_V3_1_NON_CANCER: exact variant query 13-32370464-TAG-AA, search_status absent; evidence sentence: Absent from gnomAD v3.1 non-cancer.
Still missing
  • No exact variant entry found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt for c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22.
  • No exact variant entry found in Specifications_V1.2_2024-11-18.docx.txt for c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22.
  • No exact variant entry found in Appendices_V1.2_2024-11-18.docx.txt for c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22.
  • No exact variant entry found in HUMU-40-1557-s001.xlsx.txt for c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗gnomad_v2 ↗gnomad_v4 ↗

Not assessed · 9 · no assessment recorded

PS3 VCEPNot assessed: no exact-variant protein functional assay or pre-assigned Table 9 code was found in the five governing VCEP files. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 VCEP reserves PS3 for well-established functional studies measuring protein function alone or mRNA and protein together, and directs curators to calibrated published assay recommendations in Table 9. The exact variant was not found under c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22 in SupplementaryTables_V1.2_2024-11-18.xlsx, Specifications_V1.2_2024-11-18.docx, Appendices_V1.2_2024-11-18.docx, HUMU-40-1557-s001.xlsx, or Specifications_Table9_V1.2_2024-11-18.xlsx. The reviewed PMID:22632462 extraction also states that the exact variant is not mentioned and describes splice assays rather than variant-specific protein-function evidence. Therefore, PS3 cannot be assigned from the available VCEP-governed evidence.

VCEP rule
Well-established in vitro or in vivo functional studies supportive of a damaging effect. Apply PS3 for assays measuring effect via protein only OR mRNA and protein combined. See Specifications Table 9 for code recommendations from calibrated published assays.
Evidence considered
  • Specifications_V1.2_2024-11-18.docx, functional-criteria entry: PS3 is for well-established functional studies supportive of a damaging effect when the assay measures protein only or mRNA and protein combined, with calibrated recommendations in Table 9.
  • Appendices_V1.2_2024-11-18.docx, Appendix E: splicing-assay evidence is not assigned PS3 or BS3 and those codes are reserved for protein-function impact.
  • Specifications_Table9_V1.2_2024-11-18.xlsx: no row matched c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22.
  • PMID:22632462 paper extraction: the exact variant is not mentioned; the paper reports BRCA2 minigene RT-PCR splicing assays for other variants.
Still missing
  • No entry for c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22 in SupplementaryTables_V1.2_2024-11-18.xlsx.
  • No entry for c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22 in Specifications_V1.2_2024-11-18.docx.
  • No entry for c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22 in Appendices_V1.2_2024-11-18.docx.
  • No entry for c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22 in HUMU-40-1557-s001.xlsx.
  • No entry for c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22 in Specifications_Table9_V1.2_2024-11-18.xlsx.
  • No variant-specific protein-function assay result is available in the reviewed evidence.
  • The available PMID:22632462 extraction does not mention this exact variant and reports splicing assays, which the VCEP does not assign PS3 or BS3 codes.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗vcep_specifications_table9_v1_2_2024_11_18 ↗PMID:22632462 ↗
PS4 VCEPNot assessed: no variant-specific case-control counts, odds ratio, p-value, or confidence interval were available to test the PS4 thresholds. Details ▾Hide ▴
Reasoning

The ENIGMA rule requires a case-control study with p-value ≤0.05, OR ≥4, and a lower confidence interval excluding 2.0. The declared VCEP files SupplementaryTables_V1.2_2024-11-18.xlsx, Specifications_V1.2_2024-11-18.docx, and HUMU-40-1557-s001.xlsx were searched for c.8394_8396delinsAA, p.Arg2799AsnfsTer22, and p.R2799Nfs*22, with no matching variant entry. The literature_pass.json packet has no ai_classified_papers, and its PS4 index leads were checked against the available publication text; no variant-specific case-control counts, odds ratio, p-value, or confidence interval were available. Therefore PS4 cannot be evaluated rather than being treated as absent evidence.

VCEP rule
The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. Case-control studies; p-value ≤0.05 and OR ≥4 (lower confidence interval excludes 2.0). See Appendix F for details.
Evidence considered
  • Specifications_V1.2_2024-11-18.docx, PS4 rule: case-control studies require p-value ≤0.05, OR ≥4, and a lower confidence interval excluding 2.0.
  • SupplementaryTables_V1.2_2024-11-18.xlsx, searched ST/reference text under c.8394_8396delinsAA, p.Arg2799AsnfsTer22, and p.R2799Nfs*22; no matching row found.
  • HUMU-40-1557-s001.xlsx, searched HGVS coding and protein notations; no matching row found.
  • literature_pass.json, PS4 index leads 20301425, 20301471, 22776961, 26681312, 32352694, and 35924163 were checked against the available publication text; no variant-specific case-control result was available.
  • ClinVar variation 52573 reports expert-panel Pathogenic classification, but that classification is not used as PS4 evidence and does not provide the required case-control metrics here.
Still missing
  • No matching entry for c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22 in SupplementaryTables_V1.2_2024-11-18.xlsx.
  • No matching entry in HUMU-40-1557-s001.xlsx.
  • No variant-specific case-control data identified in the literature_pass.json PS4 leads or available publication text.
Sources
cspec ↗vcep_supplementarytables_v1_2_2024_11_18 ↗vcep_humu_40_1557_s001 ↗clinvar ↗PMID:22193408 ↗PMID:22632462 ↗
PM3 VCEPNot assessed: no documented Fanconi Anemia phenotype, second pathogenic BRCA2 variant, phase, or PM3 point total was available for this frameshift. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 rule requires a patient with a phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia and a co-occurrent variant in the same gene, with phase and proband-level observations scored under Table 6. The available case evidence does not document a Fanconi Anemia phenotype, chromosome-breakage result, a second pathogenic or likely pathogenic BRCA2 variant, phase, or the required proband-level PM3 points. Searches for c.8394_8396delinsAA, p.Arg2799AsnfsTer22, and p.R2799Nfs*22 found no matching entry in Specifications_V1.2_2024-11-18.docx.txt or the other BRCA2 VCEP full-text files searched. PM3 therefore cannot be assessed without substituting evidence or thresholds outside the VCEP record.

VCEP rule
For recessive disorders, detected in trans with a pathogenic variant. ... Apply for patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia (FA), and co-occurrent variants in the same gene. ... Phenotype is considered consistent with BRCA1- or BRCA2-related FA if: ... (i) Increased chromosome breakage (DEB, MMC, or spontaneous) and at least one clinical feature indicative of BRCA1/2-related FA, categorized under: physical features, pathology and laboratory findings, cancer diagnosis ≤5yr. ... (ii) Result unknown for chromosome breakage, and at least two clinical features indicative of BRCA1/2-related FA under at least two of the three categories: physical features, pathology and laboratory findings, cancer diagnosis ≤5yr. ... Variant under assessment must be sufficiently rare (not meeting a benign population evidence code). ... 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
  • ClinGen ENIGMA BRCA2 Specification v1.2, PM3 rule and Table 6: PM3 requires a qualifying BRCA1/2-related Fanconi Anemia presentation with a co-occurrent pathogenic/likely pathogenic variant in the same gene, and assigns points according to phase and phenotype.
  • The consolidated allelic case-evidence bundle contains no qualifying PM3 observation for this variant: no Fanconi Anemia phenotype, chromosome-breakage result, second BRCA2 pathogenic/likely pathogenic variant, phase, or PM3 point calculation was documented.
  • The variant notations c.8394_8396delinsAA, p.Arg2799AsnfsTer22, and p.R2799Nfs*22 were searched in the governing BRCA2 VCEP full-text corpus; no matching row was found.
Still missing
  • Specifications_V1.2_2024-11-18.docx.txt was searched for c.8394_8396delinsAA, p.Arg2799AsnfsTer22, and p.R2799Nfs*22; no matching variant entry was found.
  • The case evidence bundle does not provide a qualifying Fanconi Anemia phenotype, chromosome-breakage result, co-occurrent pathogenic/likely pathogenic BRCA2 variant, phase determination, or Table 6 PM3 point total.
Sources
vcep_specifications_v1_2_2024_11_18 ↗
PP1 VCEPNot assessed: no quantitative co-segregation likelihood ratio or family-level genotype and phenotype data are available to compare with the VCEP's LR ≥2.08:1 threshold. Details ▾Hide ▴
Reasoning

PP1 is applicable only when co-segregation with disease in multiple affected family members is evaluated quantitatively and assigned by Bayes-score likelihood-ratio thresholds. The available case evidence contains no proband-level parental testing, affected-relative genotypes and phenotypes, meioses, pedigree, or quantitative co-segregation likelihood ratio for this variant. The searched ENIGMA files SupplementaryTables_V1.2_2024-11-18.xlsx, Specifications_V1.2_2024-11-18.docx, and HUMU-40-1557-s001.xlsx contain no entry for c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22; this is a documentation gap, not evidence against segregation.

VCEP rule
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease, as measured by a quantitative co-segregation analysis method. See Appendix I for details. ... Apply weight as per Bayes Score: ... PP1 - LR ≥2.08:1
Evidence considered
  • ENIGMA BRCA2 VCEP PP1 rule: co-segregation must involve multiple affected family members and be measured by a quantitative co-segregation analysis method; Supporting requires LR ≥2.08:1, Moderate requires LR ≥4.3:1, Strong requires LR ≥18.7:1, and Very Strong requires LR ≥350:1.
  • The case evidence bundle provides no quantitative PP1 LR, pedigree, meiosis count, parental testing, or affected-relative genotype/phenotype observations for this variant.
  • SupplementaryTables_V1.2_2024-11-18.xlsx, Specifications_V1.2_2024-11-18.docx, and HUMU-40-1557-s001.xlsx were searched under c.8394_8396delinsAA, p.Arg2799AsnfsTer22, and p.R2799Nfs*22; no matching entry was found.
Still missing
  • No proband-level parental testing, affected-relative genotype and phenotype data, meioses, pedigree, or quantitative co-segregation LR were available.
  • No entry for c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22 was found in SupplementaryTables_V1.2_2024-11-18.xlsx.
  • No entry for c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22 was found in Specifications_V1.2_2024-11-18.docx.
  • No entry for c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22 was found in HUMU-40-1557-s001.xlsx.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_supplementarytables_v1_2_2024_11_18 ↗vcep_humu_40_1557_s001 ↗
PP4 VCEPNot assessed: the Li et al. clinical-history table has no c.8394_8396delinsAA row from which to calculate or assign a PP4 likelihood-ratio strength. Details ▾Hide ▴
Reasoning

The ENIGMA rule permits PP4 only for combined clinical likelihood-ratio evidence and requires LR ≥2.08:1 for supporting, ≥4.3:1 for moderate, ≥18.7:1 for strong, or ≥350:1 for very strong. The governing Li et al. clinical-history table PMID_31853058_BRCA2_clinical_history_LR.xlsx was searched for the exact BRCA2 coding change c.8394_8396delinsAA; no row was present. The other declared PP4 files provide methodology but no variant-level LR for this variant. Accordingly, PP4 is not assessed.

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 ... See Specifications Table7 and Appendix B for details.
Evidence considered
  • Specifications_V1.2_2024-11-18.docx, Table 1 PP4 rule and thresholds: combined LR ≥2.08:1 supporting, ≥4.3:1 moderate, ≥18.7:1 strong, and ≥350:1 very strong.
  • PMID_31853058_BRCA2_clinical_history_LR.xlsx, Sheet1, exact BRCA2 HGVS_Nucleotide search for c.8394_8396delinsAA; no matching row found.
  • PMID_31853058_Li_2020_GeneticsInMedicine.pdf, PMID_31853058_methods_supplement.docx, and PMID_17924331_Easton_2007_AJHG.pdf were consulted as methodology/context sources; none supplied a variant-level LR for this variant.
Still missing
  • No exact BRCA2 c.8394_8396delinsAA row in PMID_31853058_BRCA2_clinical_history_LR.xlsx.
  • No variant-level combined clinical LR in PMID_31853058_Li_2020_GeneticsInMedicine.pdf, PMID_31853058_methods_supplement.docx, or PMID_17924331_Easton_2007_AJHG.pdf.
Sources
cspec ↗vcep_pmid_31853058_brca2_clinical_history_lr ↗PMID:31853058 ↗vcep_pmid_31853058_li_2020_geneticsinmedicine ↗vcep_pmid_31853058_methods_supplement ↗vcep_pmid_17924331_easton_2007_ajhg ↗PMID:17924331 ↗
BS2 VCEPNot assessed: no qualifying phenotyped trans, homozygous, age, or follow-up observation is available for the ENIGMA BS2 point system. Details ▾Hide ▴
Reasoning

BS2 cannot be assessed from the available evidence. ENIGMA BS2 requires phenotyped clinical or research-cohort observations in which the variant is in trans with a pathogenic or likely pathogenic variant, or is homozygous, in a patient presumed unaffected by Fanconi Anemia, with points assigned by age at cancer diagnosis or age at follow-up. The case evidence contains no such phase, homozygote, cohort-phenotype, age, or follow-up observation. The VCEP specifically excludes frequency-code data from BS2 scoring, so gnomAD absence cannot substitute for the required observations. The four governing VCEP full-text files were searched for c.8394_8396delinsAA, p.Arg2799AsnfsTer22, and p.R2799Nfs*22 with no exact variant entry found: 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 HUMU-40-1557-s001.xlsx.txt.

VCEP rule
Applied in absence of features of recessive disease, namely Fanconi Anemia phenotype. See Specifications Table 8 for additional stipulations, and approach to assign points per proband, and final BS2 code assignment based on the sum of BS2-related points. See Appendix H for additional details.
Evidence considered
  • No BS2-eligible clinical or research-cohort observation was present in the case evidence; gnomAD records were not used for BS2 scoring because the VCEP excludes frequency-code data from BS2 point assignment.
Still missing
  • No qualifying BS2 clinical or research-cohort observation with phase, homozygous status, age at cancer diagnosis, or age at last follow-up.
  • No exact variant entry found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt for c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22.
  • No exact variant entry found in Specifications_V1.2_2024-11-18.docx.txt for c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22.
  • No exact variant entry found in Appendices_V1.2_2024-11-18.docx.txt for c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22.
  • No exact variant entry found in HUMU-40-1557-s001.xlsx.txt for c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗
BS3 VCEPNot assessed: no exact-variant benign protein-function assay or pre-assigned Table 9 code was found in the five governing VCEP files. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 VCEP reserves BS3 for well-established functional studies showing no damaging effect on protein function, measured through protein alone or mRNA and protein combined, and directs use of calibrated recommendations in Table 9. The exact variant was not found under c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22 in SupplementaryTables_V1.2_2024-11-18.xlsx, Specifications_V1.2_2024-11-18.docx, Appendices_V1.2_2024-11-18.docx, HUMU-40-1557-s001.xlsx, or Specifications_Table9_V1.2_2024-11-18.xlsx. The reviewed PMID:22632462 extraction does not mention the exact variant and concerns splicing assays, not variant-specific benign protein-function evidence. Therefore, BS3 cannot be assigned from the available VCEP-governed evidence.

VCEP rule
Well-established in vitro or in vivo functional studies shows no damaging effect on protein function. Assay measures effect via protein only OR mRNA and protein combined. See Specifications Table 9 for code recommendations from calibrated published assays.
Evidence considered
  • Specifications_V1.2_2024-11-18.docx, functional-criteria entry: BS3 is for well-established functional studies showing no damaging effect on protein function when the assay measures protein only or mRNA and protein combined, with calibrated recommendations in Table 9.
  • Appendices_V1.2_2024-11-18.docx, Appendix E: splicing-assay evidence is not assigned PS3 or BS3 and those codes are reserved for protein-function impact.
  • Specifications_Table9_V1.2_2024-11-18.xlsx: no row matched c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22.
  • PMID:22632462 paper extraction: the exact variant is not mentioned; the paper reports BRCA2 minigene RT-PCR splicing assays for other variants.
Still missing
  • No entry for c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22 in SupplementaryTables_V1.2_2024-11-18.xlsx.
  • No entry for c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22 in Specifications_V1.2_2024-11-18.docx.
  • No entry for c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22 in Appendices_V1.2_2024-11-18.docx.
  • No entry for c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22 in HUMU-40-1557-s001.xlsx.
  • No entry for c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22 in Specifications_Table9_V1.2_2024-11-18.xlsx.
  • No variant-specific benign protein-function assay result is available in the reviewed evidence.
  • The available PMID:22632462 extraction does not mention this exact variant and reports splicing assays, which the VCEP does not assign PS3 or BS3 codes.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗vcep_specifications_table9_v1_2_2024_11_18 ↗PMID:22632462 ↗
BS4 VCEPNot assessed: no quantitative non-segregation likelihood ratio or affected-relative genotype and phenotype data are available to compare with the VCEP's LR ≤0.48:1 threshold. Details ▾Hide ▴
Reasoning

BS4 is applicable only when lack of segregation in affected family members is evaluated quantitatively and assigned by Bayes-score likelihood-ratio thresholds. The available case evidence contains no affected-relative genotypes and phenotypes, pedigree, non-segregation observations, meioses, or quantitative BS4 likelihood ratio for this variant. The searched ENIGMA files SupplementaryTables_V1.2_2024-11-18.xlsx, Specifications_V1.2_2024-11-18.docx, and HUMU-40-1557-s001.xlsx contain no entry for c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22; this is a documentation gap, not evidence of segregation failure.

VCEP rule
Lack of segregation in affected members of a family, as measured by a quantitative co-segregation analysis method. See Appendix I for details. ... Apply weight as per Bayes Score: ... BS4\_Supporting - LR ≤0.48:1
Evidence considered
  • ENIGMA BRCA2 VCEP BS4 rule: lack of segregation in affected family members must be measured by a quantitative co-segregation analysis method; Supporting requires LR ≤0.48:1, Moderate requires LR ≤0.23:1, Strong requires LR ≤0.05:1, and Very Strong requires LR ≤0.00285:1.
  • The case evidence bundle provides no quantitative BS4 LR, pedigree, meiosis count, non-segregating affected relatives, or affected-relative genotype/phenotype observations for this variant.
  • SupplementaryTables_V1.2_2024-11-18.xlsx, Specifications_V1.2_2024-11-18.docx, and HUMU-40-1557-s001.xlsx were searched under c.8394_8396delinsAA, p.Arg2799AsnfsTer22, and p.R2799Nfs*22; no matching entry was found.
Still missing
  • No affected-relative genotype and phenotype data, pedigree, meioses, non-segregation observations, or quantitative BS4 LR were available.
  • No entry for c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22 was found in SupplementaryTables_V1.2_2024-11-18.xlsx.
  • No entry for c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22 was found in Specifications_V1.2_2024-11-18.docx.
  • No entry for c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22 was found in HUMU-40-1557-s001.xlsx.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_supplementarytables_v1_2_2024_11_18 ↗vcep_humu_40_1557_s001 ↗
BP5 VCEPNot assessed: no variant-level clinical likelihood ratio was found to test the BP5 supporting threshold LR ≤0.48:1 or stronger thresholds. Details ▾Hide ▴
Reasoning

The ENIGMA rule restricts BP5 to combined multifactorial clinical LR against pathogenicity, with the supporting threshold LR ≤0.48:1, moderate threshold LR ≤0.23:1, strong threshold LR ≤0.05:1, and very strong threshold LR ≤0.00285:1. The governing Li et al. BRCA2 clinical-history table was searched for c.8394_8396delinsAA and contained no matching row, so no LR is available for the required explicit comparison. BP5 is therefore not assessed.

VCEP rule
Use ONLY to capture combined LR against pathogenicity, based on multifactorial likelihood clinical data. ... BP5 - LR ≤0.48:1 ... Not applicable for co-observation: cases with pathogenic variants in two (or more) different known breast–ovarian cancer risk genes have no specific phenotype.
Evidence considered
  • Specifications_V1.2_2024-11-18.docx, BP5 rule: use only combined LR against pathogenicity; BP5 ≤0.48:1, BP5_Moderate ≤0.23:1, BP5_Strong ≤0.05:1, and BP5_VeryStrong ≤0.00285:1.
  • Explicit threshold-direction check: no variant LR is available, so an inequality such as LR ≤0.48:1 cannot be evaluated.
  • PMID_31853058_BRCA2_clinical_history_LR.xlsx, Sheet1, exact BRCA2 HGVS_Nucleotide search for c.8394_8396delinsAA; no matching row found.
  • PMID_17924331_Easton_2007_AJHG.pdf, methodology/context source; no variant-level LR for this variant was available.
Still missing
  • No exact BRCA2 c.8394_8396delinsAA row in PMID_31853058_BRCA2_clinical_history_LR.xlsx.
  • No combined clinical LR for this variant in the declared Li et al. or Easton methodology sources.
Sources
cspec ↗vcep_pmid_31853058_brca2_clinical_history_lr ↗PMID:31853058 ↗vcep_pmid_17924331_easton_2007_ajhg ↗PMID:17924331 ↗
Not applicable · 14· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/ANot applicable: the variant is a frameshift, whereas ENIGMA PS1 applies to same-missense or same-predicted-splicing variants. Details ▾Hide ▴
Reasoning

The variant is a frameshift, NM_000059.4:c.8394_8396delinsAA, p.(Arg2799AsnfsTer22), not a predicted missense substitution. The ENIGMA BRCA2 PS1 rule applies to predicted missense substitutions or variants with the same predicted splicing impact as a previously classified pathogenic or likely pathogenic variant; neither route applies to this frameshift, and no exact notation for this variant was found in the searched governing VCEP files.

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
  • Case normalization identifies NM_000059.4:c.8394_8396delinsAA as NP_000050.3:p.(Arg2799AsnfsTer22), a frameshift in exon 19.
  • The governing ENIGMA PS1 rule distinguishes predicted missense substitutions and variants with the same predicted splicing impact; this frameshift is neither route.
Still missing
  • No exact c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22 entry was found in Specifications_V1.2_2024-11-18.docx or the other searched BRCA2 VCEP files; this does not change the variant-type exclusion from PS1.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗
PS2 VCEPNot applicable: the ENIGMA BRCA2 VCEP does not permit PS2 because de novo occurrence has not been calibrated for these relatively common cancers. Details ▾Hide ▴
Reasoning

PS2 is not applicable under the ENIGMA BRCA2 VCEP specification because the VCEP states that BRCA1/2-related cancers occur relatively commonly and provides no information to calibrate the predictive capacity of de novo occurrences.

VCEP rule
BRCA1/2-related cancers occur relatively commonly. No information to calibrate the predictive capacity of de novo occurrences.
Evidence considered
  • ENIGMA BRCA2 VCEP specification, PS2: the criterion is marked not applicable because BRCA1/2-related cancers occur relatively commonly and no information is available to calibrate the predictive capacity of de novo occurrences.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗
PM1 VCEPNot applicable: ENIGMA explicitly prohibits PM1 and routes domain evidence through PP3/BP4, despite residue 2799 lying within DNA-binding aa 2481-3186. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 specification explicitly states that PM1 is not used and is considered as a component of the PP3/BP4 bioinformatic analysis. The variant is also outside the VCEP-defined BRCA2 functional domains relevant to missense/in-frame bioinformatic analysis: PALB2 binding aa 10-40 and DNA binding aa 2481-3186; residue 2799 lies within the latter, but the VCEP's explicit PM1 prohibition controls. The case vcep_materials.json domain_tables key is empty.

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
  • The ENIGMA specification states PM1: Do not use; considered as a component of bioinformatic analysis (PP3/BP4).
  • The VCEP-defined BRCA2 domains are PALB2 binding aa 10-40 and DNA binding aa 2481-3186; residue 2799 is within the DNA-binding interval, but this does not override the explicit PM1 prohibition.
  • vcep_materials.json has domain_tables: {} for this case.
Still missing
  • No exact c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22 entry was found in Specifications_V1.2_2024-11-18.docx, Appendices_V1.2_2024-11-18.docx, SupplementaryTables_V1.2_2024-11-18.xlsx, or Specifications_Table4_V1.2_2024-11-18.xlsx; PM1 is nevertheless explicitly not used by the VCEP.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗
PM2 N/ANot applicable: ENIGMA excludes delins variants from PM2, despite the exact variant being absent from gnomAD v2.1 and v3.1 non-cancer datasets. Details ▾Hide ▴
Reasoning

PM2 is not applicable because the assessed variant is a delins. Although the exact variant is absent from the specified gnomAD non-cancer datasets, the ENIGMA rule explicitly excludes insertion, deletion, and delins variants from PM2 application; therefore absence and the unavailable depth metric do not support PM2. The four governing VCEP full-text files were searched for c.8394_8396delinsAA, p.Arg2799AsnfsTer22, and p.R2799Nfs*22 with no exact variant entry found: 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 HUMU-40-1557-s001.xlsx.txt.

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
  • GNOMAD_V2_1_NON_CANCER: exact variant query 13-32944601-TAG-AA, search_status absent; evidence sentence: Absent from gnomAD v2.1 non-cancer.
  • GNOMAD_V3_1_NON_CANCER: exact variant query 13-32370464-TAG-AA, search_status absent; evidence sentence: Absent from gnomAD v3.1 non-cancer.
  • Variant consequence is frameshift/delins: NM_000059.4:c.8394_8396delinsAA, p.(Arg2799AsnfsTer22).
Still missing
  • Average read depth around the variant is not reported, although depth cannot override the VCEP's explicit delins exclusion.
  • No exact variant entry found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt for c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22.
  • No exact variant entry found in Specifications_V1.2_2024-11-18.docx.txt for c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22.
  • No exact variant entry found in Appendices_V1.2_2024-11-18.docx.txt for c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22.
  • No exact variant entry found in HUMU-40-1557-s001.xlsx.txt for c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗gnomad_v2 ↗gnomad_v4 ↗
PM4 VCEPNot applicable: the ENIGMA BRCA2 specification says PM4 is not used and captures protein-length analysis through PP3/BP4 instead. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 VCEP explicitly instructs that PM4 is not used and that protein length changes are captured as part of bioinformatic analysis. This frameshift is therefore not assigned PM4 under the governing specification.

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 Specifications Table 1, PM4 row: 'Do not use'; protein length changes are 'Considered as component of bioinformatic analysis (PP3/BP4).'
Still missing
  • No exact c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22 entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No exact c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22 entry was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No exact c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22 entry was found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt.
  • No exact c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22 entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗
PM6 VCEPNot applicable: the ENIGMA BRCA2 VCEP does not permit PM6 because de novo occurrence has not been calibrated for these relatively common cancers. Details ▾Hide ▴
Reasoning

PM6 is not applicable under the ENIGMA BRCA2 VCEP specification because the VCEP states that BRCA1/2-related cancers occur relatively commonly and provides no information to calibrate the predictive capacity of de novo occurrences.

VCEP rule
BRCA1/2-related cancers occur relatively commonly. No information to calibrate the predictive capacity of de novo occurrences.
Evidence considered
  • ENIGMA BRCA2 VCEP specification, PM6: the criterion is marked not applicable because BRCA1/2-related cancers occur relatively commonly and no information is available to calibrate the predictive capacity of de novo occurrences.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗
PP2 VCEPNot applicable: ENIGMA does not use PP2 for BRCA2, and this variant is a frameshift rather than a missense variant. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 specification explicitly says PP2 is not used because of a high frequency of benign missense variants. In addition, this case variant is a frameshift rather than a missense variant, so it is outside the criterion's named 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 High frequency of benign missense variants.
Evidence considered
  • The governing ENIGMA PP2 entry states Do not use and gives high frequency of benign missense variants as the reason.
  • The case variant is a frameshift, not a missense variant.
Still missing
  • No exact c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22 entry was found in the searched BRCA2 VCEP files; no PP2 evidence can be applied under the VCEP rule.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗
PP3 N/ANot applicable: the ENIGMA PP3 rule covers missense, in-frame, silent, or eligible intronic variants, whereas this variant is a frameshift. Details ▾Hide ▴
Reasoning

The variant is a frameshift, c.8394_8396delinsAA, p.(Arg2799AsnfsTer22), in exon 19. The ENIGMA BRCA2 PP3 rule covers missense/in-frame variants for protein predictions and silent, missense/in-frame, or eligible intronic variants for splice predictions; frameshift variants are outside that scope. The VCEP files searched were Specifications_V1.2_2024-11-18.docx, Appendices_V1.2_2024-11-18.docx, SupplementaryTables_V1.2_2024-11-18.xlsx, and PMID_22505045_Houdayer_2012_HumMutat.pdf; no notation of this variant was found. SpliceAI max delta 0.13 therefore does not make PP3 applicable.

VCEP rule
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
  • Variant consequence is frameshift: NM_000059.4:c.8394_8396delinsAA, NP_000050.3:p.(Arg2799AsnfsTer22), exon 19.
  • The ENIGMA specification limits PP3 protein-impact assessment to missense or in-frame insertion, deletion, or delins variants and limits PP3 splice assessment to silent, missense/in-frame, or eligible intronic variants; frameshift is not included.
  • SpliceAI reported a maximum delta score of 0.13, but this score is not adjudicative because the variant is outside PP3 scope.
  • The four governing VCEP full-text files named for this group were searched under all three supplied variant notations with no matching entry.
Still missing
  • No entry for c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22 was found in Specifications_V1.2_2024-11-18.docx.
  • No entry for c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22 was found in Appendices_V1.2_2024-11-18.docx.
  • No entry for c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22 was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No entry for c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22 was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗
BP1 N/ANot applicable: BP1 covers silent, missense, or in-frame indel variants, whereas this variant is a frameshift. Details ▾Hide ▴
Reasoning

The ENIGMA BP1 application is limited to silent substitutions, missense variants, or in-frame insertion/deletion/delins variants outside a clinically important functional domain with SpliceAI ≤0.1. This variant is a frameshift, not one of the eligible variant types, so BP1 cannot be applied.

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
  • The governing BP1 rule applies to silent substitution, missense, or in-frame insertion/deletion/delins variants outside a clinically important functional domain and requires SpliceAI ≤0.1.
  • The case variant is a frameshift in exon 19, so it is outside the BP1-eligible variant types.
Still missing
  • No exact c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22 entry was found in Specifications_V1.2_2024-11-18.docx or the other searched BRCA2 VCEP files; the variant type independently excludes BP1.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗
BP2 VCEPNot applicable: ENIGMA BRCA2 explicitly says BP2 is not used and limits it to the BS2 context. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 specification explicitly says not to use BP2 and states that it is applied only in the context of BS2. Therefore BP2 is not applicable for this VCEP-only adjudication, regardless of whether phase or co-occurrence data exist.

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
  • ClinGen ENIGMA BRCA2 Specification v1.2, BP2 entry: the criterion is explicitly marked 'Do not use' and 'Applied only in the context of BS2.'
Sources
vcep_specifications_v1_2_2024_11_18 ↗
BP3 VCEPNot applicable: BP3 is a criterion the ENIGMA specification says not to use, and this variant is a frameshift. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 VCEP explicitly instructs that BP3 is not used and that the repetitive-region concept is captured by bioinformatic prediction and domain analysis. The submitted variant is a frameshift rather than an in-frame insertion or deletion, so BP3 is not applicable under the VCEP specification.

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 Specifications Table 1, BP3 row: 'Do not use'; the criterion is captured by bioinformatic tool prediction and domain analysis.
Still missing
  • No exact c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22 entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No exact c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22 entry was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No exact c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22 entry was found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt.
  • No exact c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22 entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗
BP4 N/ANot applicable: ENIGMA BP4 is restricted to missense/in-frame, silent, or eligible intronic variants, and this variant is a frameshift. Details ▾Hide ▴
Reasoning

The variant is a frameshift, c.8394_8396delinsAA, p.(Arg2799AsnfsTer22), in exon 19. The ENIGMA BP4 rule applies to missense/in-frame variants in a functional domain, silent variants in a functional domain, or intronic variants outside donor and acceptor ±1,2 positions; frameshifts are outside BP4 scope. Consistent with the requested VCEP interpretation, a no-splice-impact result cannot negate the truncating protein consequence. The VCEP files searched were Specifications_V1.2_2024-11-18.docx, Appendices_V1.2_2024-11-18.docx, SupplementaryTables_V1.2_2024-11-18.xlsx, and PMID_22505045_Houdayer_2012_HumMutat.pdf; no notation of this variant was found.

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
  • Variant consequence is frameshift: NM_000059.4:c.8394_8396delinsAA, NP_000050.3:p.(Arg2799AsnfsTer22), exon 19.
  • The ENIGMA specification limits BP4 to missense/in-frame variants, silent variants, and eligible intronic variants; frameshift variants are not included.
  • SpliceAI reported a maximum delta score of 0.13, but a no-splice-impact result cannot establish no impact on the gene product for a frameshift and is not adjudicative for BP4.
  • The four governing VCEP full-text files named for this group were searched under all three supplied variant notations with no matching entry.
Still missing
  • No entry for c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22 was found in Specifications_V1.2_2024-11-18.docx.
  • No entry for c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22 was found in Appendices_V1.2_2024-11-18.docx.
  • No entry for c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22 was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No entry for c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22 was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗
BP6 VCEPNot applicable: the ENIGMA BRCA2 specification explicitly states that BP6 is not to be used. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 specification explicitly marks BP6 as Do not use, so no benign report is converted into BP6.

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 row: reputable-source benign reports are followed by the specification instruction Do not use.
  • ClinVar variation 52573 is Pathogenic rather than benign, and in any event the governing VCEP BP6 rule prohibits applying BP6.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗clinvar ↗
BP7 N/ANot applicable: ENIGMA BP7 is restricted to silent or eligible intronic variants with BP4 met, whereas this variant is a frameshift. Details ▾Hide ▴
Reasoning

The variant is a frameshift, c.8394_8396delinsAA, p.(Arg2799AsnfsTer22), in exon 19. The ENIGMA BP7 rule is restricted to silent variants or eligible intronic variants, with BP4 met; a frameshift is outside that scope. The VCEP files searched were Specifications_V1.2_2024-11-18.docx, Appendices_V1.2_2024-11-18.docx, SupplementaryTables_V1.2_2024-11-18.xlsx, and PMID_22505045_Houdayer_2012_HumMutat.pdf; no notation of this variant was found.

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
  • Variant consequence is frameshift: NM_000059.4:c.8394_8396delinsAA, NP_000050.3:p.(Arg2799AsnfsTer22), exon 19.
  • The ENIGMA specification limits BP7 to silent variants inside a functional domain or intronic variants at or beyond +7/-21, and requires BP4; frameshift variants are not included.
  • The four governing VCEP full-text files named for this group were searched under all three supplied variant notations with no matching entry.
Still missing
  • No entry for c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22 was found in Specifications_V1.2_2024-11-18.docx.
  • No entry for c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22 was found in Appendices_V1.2_2024-11-18.docx.
  • No entry for c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22 was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No entry for c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22 was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗

Identifiers

Gene
BRCA2
Transcript
NM_000059.4
Coding (HGVS c.)
NM_000059.4:c.8394_8396delinsAA
Protein (HGVS p.)
NP_000050.3:p.(Arg2799AsnfsTer22)
GRCh38
chr13:32370464 TAG>AA
GRCh37
chr13:32944601 TAG>AA
Location and type
Exon 19 · frameshift
ClinVar
52573

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

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +3 bp
0.038
SpliceAI acceptor gainat +36 bp
0.130
SpliceAI donor lossat +93 bp
0.014
SpliceAI donor gainat -372 bp
0.000
Pangolin splice lossmagnitude shown
-0.081
Pangolin splice gain
0.141

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 N/ANot applicable: the ENIGMA PP3 rule covers missense, in-frame, silent, or eligible intronic variants, whereas this variant is a frameshift. Details ▾Hide ▴
Reasoning

The variant is a frameshift, c.8394_8396delinsAA, p.(Arg2799AsnfsTer22), in exon 19. The ENIGMA BRCA2 PP3 rule covers missense/in-frame variants for protein predictions and silent, missense/in-frame, or eligible intronic variants for splice predictions; frameshift variants are outside that scope. The VCEP files searched were Specifications_V1.2_2024-11-18.docx, Appendices_V1.2_2024-11-18.docx, SupplementaryTables_V1.2_2024-11-18.xlsx, and PMID_22505045_Houdayer_2012_HumMutat.pdf; no notation of this variant was found. SpliceAI max delta 0.13 therefore does not make PP3 applicable.

VCEP rule
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
  • Variant consequence is frameshift: NM_000059.4:c.8394_8396delinsAA, NP_000050.3:p.(Arg2799AsnfsTer22), exon 19.
  • The ENIGMA specification limits PP3 protein-impact assessment to missense or in-frame insertion, deletion, or delins variants and limits PP3 splice assessment to silent, missense/in-frame, or eligible intronic variants; frameshift is not included.
  • SpliceAI reported a maximum delta score of 0.13, but this score is not adjudicative because the variant is outside PP3 scope.
  • The four governing VCEP full-text files named for this group were searched under all three supplied variant notations with no matching entry.
Still missing
  • No entry for c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22 was found in Specifications_V1.2_2024-11-18.docx.
  • No entry for c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22 was found in Appendices_V1.2_2024-11-18.docx.
  • No entry for c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22 was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No entry for c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22 was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗
BP4 N/ANot applicable: ENIGMA BP4 is restricted to missense/in-frame, silent, or eligible intronic variants, and this variant is a frameshift. Details ▾Hide ▴
Reasoning

The variant is a frameshift, c.8394_8396delinsAA, p.(Arg2799AsnfsTer22), in exon 19. The ENIGMA BP4 rule applies to missense/in-frame variants in a functional domain, silent variants in a functional domain, or intronic variants outside donor and acceptor ±1,2 positions; frameshifts are outside BP4 scope. Consistent with the requested VCEP interpretation, a no-splice-impact result cannot negate the truncating protein consequence. The VCEP files searched were Specifications_V1.2_2024-11-18.docx, Appendices_V1.2_2024-11-18.docx, SupplementaryTables_V1.2_2024-11-18.xlsx, and PMID_22505045_Houdayer_2012_HumMutat.pdf; no notation of this variant was found.

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
  • Variant consequence is frameshift: NM_000059.4:c.8394_8396delinsAA, NP_000050.3:p.(Arg2799AsnfsTer22), exon 19.
  • The ENIGMA specification limits BP4 to missense/in-frame variants, silent variants, and eligible intronic variants; frameshift variants are not included.
  • SpliceAI reported a maximum delta score of 0.13, but a no-splice-impact result cannot establish no impact on the gene product for a frameshift and is not adjudicative for BP4.
  • The four governing VCEP full-text files named for this group were searched under all three supplied variant notations with no matching entry.
Still missing
  • No entry for c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22 was found in Specifications_V1.2_2024-11-18.docx.
  • No entry for c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22 was found in Appendices_V1.2_2024-11-18.docx.
  • No entry for c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22 was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No entry for c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22 was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗
BP7 N/ANot applicable: ENIGMA BP7 is restricted to silent or eligible intronic variants with BP4 met, whereas this variant is a frameshift. Details ▾Hide ▴
Reasoning

The variant is a frameshift, c.8394_8396delinsAA, p.(Arg2799AsnfsTer22), in exon 19. The ENIGMA BP7 rule is restricted to silent variants or eligible intronic variants, with BP4 met; a frameshift is outside that scope. The VCEP files searched were Specifications_V1.2_2024-11-18.docx, Appendices_V1.2_2024-11-18.docx, SupplementaryTables_V1.2_2024-11-18.xlsx, and PMID_22505045_Houdayer_2012_HumMutat.pdf; no notation of this variant was found.

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
  • Variant consequence is frameshift: NM_000059.4:c.8394_8396delinsAA, NP_000050.3:p.(Arg2799AsnfsTer22), exon 19.
  • The ENIGMA specification limits BP7 to silent variants inside a functional domain or intronic variants at or beyond +7/-21, and requires BP4; frameshift variants are not included.
  • The four governing VCEP full-text files named for this group were searched under all three supplied variant notations with no matching entry.
Still missing
  • No entry for c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22 was found in Specifications_V1.2_2024-11-18.docx.
  • No entry for c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22 was found in Appendices_V1.2_2024-11-18.docx.
  • No entry for c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22 was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No entry for c.8394_8396delinsAA, p.Arg2799AsnfsTer22, or p.R2799Nfs*22 was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.13).

8 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.
    No paper-specific finding is recorded.
    PMID 10570174 ↗
  • BRCA2 is required for homology-directed repair of chromosomal breaks.
    No paper-specific finding is recorded.
    PMID 11239455 ↗
  • A new mutation of BRCA2 gene in an Italian healthy woman with familial breast cancer history.
    No paper-specific finding is recorded.
    PMID 20878484 ↗
  • BRCA1 and BRCA2: different roles in a common pathway of genome protection.
    The paper does not mention BRCA2 c.8394_8396delinsAA or p.(R2799Nfs*22) specifically and provides no variant-specific case-control or phenotype-likelihood evidence.
    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.
    No paper-specific finding is recorded.
    PMID 24312913 ↗
  • Comprehensive splicing functional analysis of DNA variants of the BRCA2 gene by hybrid minigenes.
    Acedo A et al. · 2012
    The paper does not explicitly mention BRCA2 c.8394_8396delinsAA or p.(R2799Nfs*22). It evaluated other BRCA2 variants in exons 19, 20, 23, and 24 using computational splice-site analysis and BRCA2 minigene RT-PCR assays; it therefore does not provide variant-specific PS3 or BS3 protein-function evidence for this case.
    Does not name this variant
    PMID 22632462 ↗
    Quoted passage
    A total of 41 variants (26.5%) were preselected and generated by PCR mutagenesis in the wt minigenes 19-20 and 23-24. Splicing functional assays were carried out by semiquantitative fluorescent RT-PCR and the peak areas of the different isoforms were quantified. Eighteen variants (43.9%) produced aberrant splicing patterns (Table 1, Figure 1 and Additional file 1, Figure S2)

    Abstract

  • Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers.
    No paper-specific finding is recorded.
    PMID 23918944 ↗
  • Central European BRCA2 mutation carriers: birth cohort status correlates with onset of breast cancer.
    Tea MK et al. · 2014
    No paper-specific finding is recorded.
    PMID 24156927 ↗

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 0.130 Open source ↗
ClinVar 9 Pathogenic 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

Absent from gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Pathogenic (9 clinical laboratories) and as Pathogenic by Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) (expert panel). (ClinVarID = 52573)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.13).

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.