Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.
This variantScenario
BenignPathogenic
Likely pathogenic.A likely pathogenic classification under the recorded framework.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
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.
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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.
Met (Very Strong): frameshift creates a premature stop at codon 613 in exon 11, predicted to trigger nonsense-mediated decay.
PP5Supporting
PP5 · supporting
Met (Supporting): the ENIGMA expert panel classifies this variant as Pathogenic in ClinVar.
Benign criteria applied · 1
BS1Supporting
BS1 · supporting
Met (Supporting): gnomAD v2.1 grpmax frequency of 2.96x10^-5 falls within the benign supporting frequency range.
Recorded classification: Likely pathogenic
Very Strong loss-of-function evidence (PVS1) plus supporting pathogenic (PP5) and supporting benign (BS1) evidence combine to a net score of 8, yielding Likely Pathogenic under the ENIGMA point system.
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
15 / 1,601,250 alleles
gnomAD v4.1: 15 / 1,601,250 alleles. Recorded AF 9.36768e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.4467e-05; MAF= 0.00345%, 8/232106 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000111607; MAF= 0.01116%, 3/26880 alleles, homozygotes = 0); grpmax FAF= 2.955e-05.
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 · 12 not assessed · 11 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
PVS1 (Very Strong, met): frameshift deletion NM_000059.4:c.1813del produces p.(Ile605TyrfsTer9), a premature termination codon predicted to trigger NMD, in a gene (BRCA2) with an ENIGMA-confirmed loss-of-function disease mechanism; no downgrade factors (last-exon escape, exon skipping rescue, non-critical distal region, population LoF enrichment) identified.
PM4 (not_applicable): variant is a frameshift/null variant, not an in-frame indel or stop-loss causing a discrete protein length change; already fully captured by PVS1.
BP3 (not_applicable): ENIGMA BRCA2 CSPEC v1.2 explicitly marks BP3 as Not Applicable for this gene, and the variant is not an in-frame indel in a repetitive region regardless.
Governing framework: ClinGen ENIGMA BRCA1/BRCA2 VCEP Specification v1.2 (cspec), which explicitly overrides generic ACMG for PS2 and PM6, marking both as globally Not Applicable for this gene due to lack of calibration data for de novo occurrence prediction in a common cancer-predisposition gene.
PP1 and BS4 remain applicable under the VCEP but require a quantitative co-segregation Bayes LR specific to this variant (per Appendix I / HUMU-40-1557-s001.xlsx multifactorial dataset); no such variant-specific segregation LR, pedigree, or family study data was found anywhere in this case's evidence bundle, so both are returned as not_assessed pending that data rather than assumed met or not_met.
This appears to be a general variant-classification lookup rather than a specific-patient case: no proband demographic, pedigree, trio, or family-history data is present in review_manifest.json, case_summary.json, or evidence.json.
NM_000059.4:c.1813del (p.Ile605TyrfsTer9) is a frameshift/null variant. Under the ENIGMA BRCA1/2 VCEP specification v1.2, functional-assay-based PS3/BS3 code application is scoped via Specifications Table 9 to missense and synonymous variant types only; this scope restriction, combined with the complete absence of any variant-specific functional assay data (protein, mRNA/splicing, or HDR) for c.1813del in the gene-VCEP materials or literature pass, means PS3 and BS3 are not applicable to this variant. General BRCA2 mechanism papers retrieved by OncoKB do not mention this variant and were excluded per strict citation-grounding rules. A superficially similar entry for c.1813dupA (a distinct duplication variant with a different frameshift) in HUMU-40-1557-s001 SuppT9 was explicitly excluded as it is not the same variant.
PS4 and PP4 both require quantitative variant-specific data (case-control OR/p-value for PS4; clinical-history LR for PP4) per ENIGMA BRCA2 v1.2, and neither is present in the consolidated evidence bundle for c.1813del despite candidate PMIDs being flagged by literature triage; both are returned not_assessed with the specific missing-data gap documented rather than inferred or guessed.
BP5 similarly lacks the required clinical-history LR data and is returned not_assessed.
PP5 is applied at supporting strength based on the exact-variant ClinVar 3-star ENIGMA expert-panel Pathogenic classification, per the case's global PP5/BP6 policy which overrides the ENIGMA VCEP's own internal 'Not Applicable' flag for PP5 (a flag intended to prevent ENIGMA from double-counting its own panel decision within its own scoring framework, not to negate the general PP5/BP6 rule applied at this pipeline's evidence-group level).
BP6 is not_applicable because no benign-direction expert-panel classification exists for this variant.
Governing framework: ClinGen ENIGMA BRCA1/BRCA2 Expert Panel Specification v1.2 (cspec), which explicitly overrides generic ACMG PM3/BP2 with a Fanconi-Anemia-phenotype/co-occurrence point-scoring system for PM3, and marks BP2 not applicable outright.
PM3 could not be scored because no proband-level Fanconi Anemia phenotype, chromosome breakage assay, or co-occurrent second BRCA2 variant/phase data was present anywhere in the consolidated case-evidence bundle.
BP2 is not applicable per the VCEP specification regardless of case-specific data.
NM_000059.4:c.1813del is a frameshift deletion (NP_000050.3:p.(Ile605TyrfsTer9)), not a missense, synonymous, in-frame indel, or intronic variant.
The governing ClinGen ENIGMA BRCA1/BRCA2 VCEP Specifications v1.2 (source_registry key 'cspec') restrict PP3, BP4, and BP7 bioinformatic-evidence application to specific variant classes (missense, in-frame indel, silent/synonymous, and intronic-outside-consensus-splice-site) using BayesDel no-AF and SpliceAI thresholds; frameshift out-of-frame deletions are not among these classes and are instead evaluated via the PVS1 null-variant pathway.
SpliceAI was still checked for completeness (DS_AG=0.0, DS_AL=0.0, DS_DG=0.018, DS_DL=0.014, max delta=0.018) and shows no meaningful predicted splice disruption, which is well below the VCEP's own PP3 (>=0.2) and BP4 (<=0.1) splicing thresholds -- this reinforces that even under a splice-impact lens there is no signal supporting PP3, and no basis to withhold BP4-adjacent reasoning, but applicability is governed by variant class first per the VCEP flowchart.
REVEL and BayesDel scores were not available in the case bundle (both null/not found), and even if BayesDel had been reported, this variant's out-of-frame frameshift nature means it does not qualify for the missense/in-frame BayesDel-based PP3/BP4 sub-path regardless.
All three criteria (PP3, BP4, BP7) are therefore classified not_applicable rather than not_met/not_assessed, since the variant type itself is outside the scope of the bioinformatic-evidence pathway as defined by the governing gene-specific VCEP specification.
ClinGen ENIGMA BRCA1/BRCA2 v1.2 CSpec (cspec) is the governing VCEP framework and was used for all four criteria's thresholds and rules in place of generic ACMG/AMP.
gnomAD v2.1 and gnomAD v4.1 (used as best-available proxy for the VCEP-specified v3.1) both show this frameshift deletion present at very low population frequency (grpmax FAF 2.955e-05 and 1.397e-05 respectively), with zero homozygotes in either dataset, and the variant is absent from gnomAD-Canada v1.0.
The frequency is high enough that the variant is not 'absent from controls' (PM2 not met), but low enough that it falls within the BS1_Supporting band via gnomAD v2.1 grpmax FAF; it does not reach the BA1 stand-alone or BS1_Strong thresholds.
BS2 could not be assessed because the VCEP applies a proband-level Fanconi Anemia phenotype points system (Table 8) rather than a population-homozygote-count rule, and no such clinical data was available in this case's population evidence.
No criteria match.
Met · 3
PVS1Very strongMet (Very Strong): frameshift creates a premature stop at codon 613 in exon 11, predicted to trigger nonsense-mediated decay.
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Reasoning
NM_000059.4:c.1813del is a single-nucleotide frameshift deletion producing NP_000050.3:p.(Ile605TyrfsTer9) — a premature termination codon at protein position 613. The ENIGMA BRCA2 CSPEC (v1.2) designates BRCA2 as a gene with an established loss-of-function disease mechanism and provides PVS1 guidance for null variants including frameshift changes (cspec label PVS1, default strength Very Strong). Per the gene-level PVS1 gate (pvs1_gene_context.json), germline LOF is confirmed as the mechanism for BRCA2. Applying the generic ClinGen SVI PVS1 decision framework (PMC6185798) referenced for variant-level assessment (pvs1_variant_assessment.json): the PTC falls in exon 11 (the large central coding exon spanning roughly codons ~405-1004, well downstream of the exon 10/11 boundary at approximately codon 405 seen in the ENIGMA exon-decision table), which is not the terminal (27th) exon of BRCA2 and the new stop is far more than 50 bp upstream of the final exon-exon junction. NMD is therefore predicted, consistent with truncating/null-variant LOF. Exon 11 is not flagged PVS1_N/A or PM5_N/A in the ENIGMA exon table, is not known to be subject to clinically relevant alternative splicing that would rescue the frameshift, and is not enriched for benign population-observed LoF variants; it is a well-established region for pathogenic truncating BRCA2 variants. No downgrade criteria (escape from NMD, distal non-critical truncation, exon skipping rescue, biologically non-essential exon) apply, so PVS1 is applied at full Very Strong strength.
Rule
PVS1: Null variant (frameshift) in a gene with an established loss-of-function disease mechanism (BRCA2), applied per the ENIGMA/ClinGen SVI PVS1 decision flowchart considering NMD prediction and exon importance.
Evidence considered
cspec (ENIGMA BRCA2 Specification v1.2): PVS1 default strength Very Strong for null variants including frameshift in a gene with established LOF mechanism.
pvs1_gene_context.json: germline LOF mechanism confirmed for BRCA2 based on CSPEC/VCEP PVS1 guidance presence (pvs1_gene_gate = eligible).
NP_000050.3:p.(Ile605TyrfsTer9) places the premature termination codon at protein residue 613, within the large exon 11 coding region, far from the final (27th) exon-exon junction, supporting NMD prediction per the ClinGen SVI decision tree.
Specifications_Table4_V1.2_2024-11-18.xlsx (via literature_pass.json) exon 10 rows indicate the exon10/11 boundary lies near codon ~405-409; codon 613 (the new PTC) is well past this boundary and within exon 11, which is not listed among BRCA2 PVS1_N/A or PM5_N/A exons (PM5_N/A exons are E6, E12, E27; exon 11 is PM5_PTC-applicable, implying it is a recognized region for pathogenic PTC variants).
Still missing
The exact per-exon PVS1 weight row for exon 11 was not directly visible in the extracted portion of Specifications_Table4_V1.2_2024-11-18.xlsx (only exon 10 rows were captured in the literature pass excerpt); exon assignment and NMD prediction here rely on inferred BRCA2 exon/codon boundaries rather than a directly retrieved exon-11 table row.
No variant-specific mRNA/transcript study for this exact deletion was found in the fetched literature; PVS1 is applied via the DNA-based frameshift/NMD prediction pathway, not via a confirmed RNA assay.
PP5SupportingMet (Supporting): the ENIGMA expert panel classifies this variant as Pathogenic in ClinVar.
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Reasoning
Expert panel Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) classified as Pathogenic.
Rule
PP5 applied at supporting strength for exact-variant ClinVar 3-star expert-panel Pathogenic/Likely pathogenic classification (ENIGMA), per global case policy overriding VCEP-internal N/A flag.
Evidence considered
ClinVar VCV000037763 shows an ENIGMA expert-panel (SCV000282362) submission classifying NM_000059.4:c.1813del as Pathogenic, review status 'reviewed by expert panel' (3-star), date last evaluated 2016-04-22, in addition to 26 other clinical-laboratory Pathogenic submissions.
Per case policy: PP5 applies at supporting strength for any exact-variant ClinVar 3-star expert-panel Pathogenic/Likely pathogenic classification, overriding the ENIGMA VCEP's internal 'Not Applicable' flag for PP5 (which exists only to prevent double-counting within ENIGMA's own scoring, not to negate ClinVar EP evidence generally).
BS1SupportingMet (Supporting): gnomAD v2.1 grpmax frequency of 2.96x10^-5 falls within the benign supporting frequency range.
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Reasoning
ENIGMA BRCA2 v1.2 BS1 Supporting applies when grpmax FAF is >0.002% (0.00002) and ≤0.01% (0.0001) in gnomAD v2.1/v3.1, non-founder population(s). gnomAD v2.1 grpmax FAF (South Asian subpopulation) is 2.955e-05, which falls within this Supporting band. gnomAD v4.1 grpmax FAF (1.397e-05, Admixed American) falls just below the 0.00002 lower bound and would not independently qualify, but the VCEP rule allows either dataset ('and/or') to satisfy the criterion, so the qualifying gnomAD v2.1 value is sufficient for BS1_Supporting. Strong-level BS1 (FAF > 0.0001) is not met by either dataset.
gnomAD v2.1 grpmax FAF = 2.955e-05 (South Asian subpopulation, 3/26880 alleles), within the BS1_Supporting band (0.00002, 0.0001].
gnomAD v4.1 grpmax FAF = 1.397e-05 (Admixed American subpopulation, 3/56988 alleles), below the 0.00002 lower bound on its own.
Still missing
VCEP specification references gnomAD v3.1 non-cancer; this case's bundle provides gnomAD v4.1 (a superset/successor of v3.1 genomes plus expanded exomes) rather than v3.1 itself — treated as the best available proxy but flagged as a minor dataset-version mismatch.
PM2Not met: variant is present in gnomAD controls (AF up to 3.4x10^-5), so it is not absent as required.
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Reasoning
ENIGMA BRCA2 v1.2 PM2_Supporting requires the variant to be absent from controls in gnomAD v2.1 (non-cancer, exome only) and gnomAD v3.1 (non-cancer). This variant is present in both gnomAD v2.1 (AC=8/AN=232106, AF=3.4467e-05) and gnomAD v4.1 (AC=15/AN=1601250, AF=9.36768e-06), so the strict 'absent from controls' requirement is not satisfied and PM2 does not apply.
Rule
ENIGMA BRCA1/BRCA2 CSpec v1.2: PM2_Supporting — absent from controls in an outbred population from gnomAD v2.1 (non-cancer, exome only)/v3.1 (non-cancer), region read depth ≥25.
Evidence considered
gnomAD v2.1: variant present, AC=8/AN=232106, AF=3.4467e-05, not absent from controls.
gnomAD v4.1: variant present, AC=15/AN=1601250, AF=9.36768e-06, not absent from controls.
BA1Not met: highest population frequency (gnomAD grpmax FAF ~3x10^-5) is far below the 0.1% stand-alone benign threshold.
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Reasoning
ENIGMA BRCA2 v1.2 BA1 requires grpmax FAF > 0.1% (0.001) in gnomAD v2.1 (non-cancer, exome only) and/or gnomAD v3.1/v4.1 (non-cancer), non-founder population(s). Observed grpmax FAF is 2.955e-05 in gnomAD v2.1 (South Asian subpopulation, AC=8/AN=232106, 0 homozygotes) and 1.397e-05 in gnomAD v4.1 (Admixed American subpopulation, AC=15/AN=1601250, 0 homozygotes) — both roughly 30-70x below the BA1 stand-alone threshold. Variant is absent entirely from gnomAD-Canada v1.0 (HostSeq genomes). No population reaches the >0.1% BA1 threshold in any dataset queried.
gnomAD v2.1: total AF 3.4467e-05 (8/232106 alleles), highest subpopulation South Asian AF 0.000111607 (3/26880), grpmax FAF 2.955e-05, 0 homozygotes.
gnomAD v4.1: total AF 9.36768e-06 (15/1601250 alleles), highest subpopulation Admixed American AF 5.26427e-05 (3/56988), grpmax FAF 1.397e-05, 0 homozygotes.
PS1Not assessed: insufficient evidence was available to evaluate this criterion.
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Reasoning
PS1 could not be assessed because its agent did not produce valid output.
Still missing
attempt 1: Hermes timed out after 200s and left no usable output_file
attempt 2: Hermes timed out after 200s and left no usable output_file
attempt 3: Hermes timed out after 200s and left no usable output_file
PS4Not assessed: no case-control enrichment data (odds ratio or p-value) was available for this variant.
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Reasoning
ENIGMA BRCA2 v1.2 defines PS4 as Strong when a formal case-control study shows significantly increased prevalence of the variant in affected vs. control individuals (p<=0.05, OR>=4, lower CI excludes 2.0; Appendix F). The case-evidence bundle contains no case-control enrichment study, odds ratio, or p-value for NM_000059.4:c.1813del. The literature_pass.json criteria_index flags several PMIDs as candidates for PS4 (11389159, 12692171, 17392385, 23035815, 24366376, 26389258, 27854360, 29348823) but none of these have full text, abstract, or extracted data present anywhere in the bundle (not in prefetch, evidence, vcep_materials, fulltext_map, or paper_extracts) to confirm variant-specific case-control enrichment data or an OR/p-value. The ClinVar aggregate record and OncoKB entry describe qualitative classification only, not quantitative case-control counts, and per instructions must never be used to infer PS4 from another source's final classification.
Rule
ENIGMA BRCA2 v1.2 PS4 (Strong): case-control study p<=0.05 and OR>=4 (lower CI excludes 2.0); see Appendix F.
Still missing
No case-control enrichment study (OR, p-value, CI) identified for c.1813del in any retrieved source
PMIDs flagged by literature triage as PS4 candidates (11389159, 12692171, 17392385, 23035815, 24366376, 26389258, 27854360, 29348823) have no full text or extracted content in this bundle to verify variant mention or case-control data
PM1Not assessed: insufficient evidence was available to evaluate this criterion.
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Reasoning
PM1 could not be assessed because its agent did not produce valid output.
Still missing
attempt 1: Hermes timed out after 200s and left no usable output_file
attempt 2: Hermes timed out after 200s and left no usable output_file
attempt 3: Hermes timed out after 200s and left no usable output_file
PM3Not assessed: no proband-level Fanconi anemia phenotype or co-occurring variant data was available.
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Reasoning
The ENIGMA BRCA1/BRCA2 v1.2 VCEP specification defines PM3 narrowly for this gene: it applies only to a proband with a phenotype consistent with BRCA1/2-related Fanconi Anemia (FA) (increased chromosome breakage by DEB/MMC/spontaneous testing plus qualifying clinical features, or two qualifying clinical features across categories if breakage testing is unknown/absent) together with a co-occurrent (biallelic) pathogenic/likely pathogenic BRCA2 variant, scored per Specifications Table 6 to determine strength (Supporting=1pt, Moderate=2pt, Strong>=4pt). The case-evidence bundle for this case (case_summary.json, evidence.json, literature_pass.json, vcep_materials.json) contains no proband-level clinical data: no chromosome breakage assay results, no FA-phenotype clinical features, no report of a second (co-occurrent) BRCA2 variant, and no zygosity/phase information for this individual. ClinVar/OncoKB entries retrieved for this variant are population-level classification records, not phased proband case data. Without this proband-specific information the PM3 point-based FA rule cannot be scored in either direction.
ENIGMA BRCA1/BRCA2 v1.2 VCEP specification (cspec) restricts PM3 to BRCA1/2-related Fanconi Anemia phenotype plus co-occurrent pathogenic variant, scored via Specifications Table 6 point system (Strong>=4pts, Moderate=2pts, Supporting=1pt); this is a gene-specific narrowing of the generic ACMG PM3 (trans pathogenic variant in recessive disease) rule.
Case-evidence bundle (case_summary.json, evidence.json, literature_pass.json, vcep_materials.json, prefetch.json) for this proband contains no chromosome breakage assay data, no FA-phenotype clinical features, and no documented second/co-occurrent BRCA2 variant or phase information.
Still missing
No chromosome breakage (DEB/MMC/spontaneous) assay result available for the proband carrying this variant.
No documented Fanconi-Anemia-consistent clinical features (physical, pathology/laboratory, or early-onset cancer diagnosis) for this proband in the case bundle.
No report of a second (trans) BRCA2 pathogenic/likely pathogenic variant co-occurring with c.1813del in this proband.
No family/proband genotype-phenotype table (e.g. Specifications Table 6 style scoring) was retrieved for this case.
PM5Not assessed: insufficient evidence was available to evaluate this criterion.
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Reasoning
PM5 could not be assessed because its agent did not produce valid output.
Still missing
attempt 1: Hermes timed out after 200s and left no usable output_file
attempt 2: Hermes timed out after 200s and left no usable output_file
attempt 3: Hermes timed out after 200s and left no usable output_file
PP1Not assessed: no family segregation data or likelihood ratio was available for this variant.
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Reasoning
The ENIGMA BRCA1/BRCA2 VCEP specification defines PP1 as applicable and requires a quantitative co-segregation Bayes LR analysis (Supporting LR>=2.08, Moderate LR>=4.3, Strong LR>=18.7, Very Strong LR>=350; see Appendix I). The case-evidence bundle for this specific variant (NM_000059.4:c.1813del / p.(Ile605TyrfsTer9)) contains no proband-specific pedigree, family segregation study, or quantitative segregation LR data. The ENIGMA multifactorial likelihood tables provided in vcep_materials (HUMU-40-1557-s001.xlsx SuppT1) were only spot-checked for two unrelated missense variants (c.1814T>C and c.8023A>G) as illustrative rows in the pre-extracted summary and did not contain a row for c.1813del; no segregation LR value for this specific frameshift variant was located in any source in the bundle. None of the fetched full-text papers (PMID:10570174, 11239455, 20878484, 22193408, 24312913, 11802209, 18824701, 19016756) mention this variant by name or report a family segregation analysis of it (paper_extracts.json is empty for this case, and the literature_pass.json PP1 candidate PMIDs 23035815/27062684/29348823 were not fetched/present in fulltext_map or source_registry for this case).
Rule
ENIGMA BRCA1/2 VCEP Specification v1.2, Table 1 (PP1): Bayes LR thresholds Supporting>=2.08:1, Moderate>=4.3:1, Strong>=18.7:1, Very Strong>=350:1
Evidence considered
ENIGMA BRCA1/BRCA2 VCEP Specification v1.2, Table 1: PP1 requires quantitative co-segregation Bayes LR analysis with thresholds Supporting>=2.08, Moderate>=4.3, Strong>=18.7, Very Strong>=350 (per Appendix I).
HUMU-40-1557-s001.xlsx (Parsons et al. 2019, PMID:31131967) SuppT1 multifactorial likelihood table contains a Segregation LR column, but the pre-extracted summary in vcep_materials.json shows no row matching c.1813del/p.(Ile605TyrfsTer9); only two unrelated missense variants (c.1814T>C, c.8023A>G) appear in the truncated preview.
No proband-specific family pedigree or segregation study data present anywhere in review_manifest.json, case_summary.json, or evidence.json for this case.
Still missing
No quantitative co-segregation LR data for NM_000059.4:c.1813del located in the ENIGMA multifactorial likelihood dataset (HUMU-40-1557-s001.xlsx) available in this case's materials
No pedigree, meiosis count, or affected-relative segregation data provided in the case bundle
Candidate PP1-relevant PMIDs identified in literature_pass.json (23035815, 27062684, 29348823) were not fetched into full text or source_registry for this case and could not be reviewed
PP2Not assessed: insufficient evidence was available to evaluate this criterion.
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Reasoning
PP2 could not be assessed because its agent did not produce valid output.
Still missing
attempt 1: Hermes timed out after 200s and left no usable output_file
attempt 2: Hermes timed out after 200s and left no usable output_file
attempt 3: Hermes timed out after 200s and left no usable output_file
PP4Not assessed: no variant-specific clinical-history likelihood ratio was available.
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Reasoning
ENIGMA BRCA2 v1.2 PP4 requires a variant-specific combined likelihood ratio (LR) from the clinical-history multifactorial model (Li et al. 2020, PMID:31853058; MOESM3/clinical_history_LR.xlsx), with Supporting at LR>=2.08, Moderate>=4.3, Strong>=18.7, Very Strong>=350. The consolidated evidence bundle includes only a truncated markdown excerpt of the Li 2020 PDF text (methodology/table headers) and does not contain a per-variant LR lookup row matching Gene=BRCA2 and HGVS_Nucleotide=c.1813del from the clinical_history_LR.xlsx source file. No variant-specific LR value for c.1813del was found in the bundle.
Rule
ENIGMA BRCA2 v1.2 PP4: clinical-history LR from Li 2020 multifactorial model. Supporting LR>=2.08, Moderate>=4.3, Strong>=18.7, Very Strong>=350 (Specifications Table7/Appendix B).
Still missing
No variant-level clinical-history LR row for c.1813del located from PMID_31853058_BRCA2_clinical_history_LR.xlsx within the provided bundle
Easton 2007 (PMID:17924331) excerpt is methodology-only text, no variant-specific LR data extracted
BS2Not assessed: no proband-level clinical data was available to score absence of Fanconi anemia features.
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Reasoning
The ENIGMA BRCA2 v1.2 BS2 rule for this gene is not the classic 'observed in healthy adult homozygote' criterion; it is a points-based system (Specifications Table 8) scoring absence of Fanconi Anemia (FA) phenotype features per proband, requiring ≥4 points for BS2_Strong. No proband-level clinical/phenotype data (chromosome breakage results, FA-associated physical/pathology/laboratory findings) is present in this case's evidence bundle to populate Table 8. gnomAD shows 0 homozygotes for this variant in both v2.1 (AN=232106) and v4.1 (AN=1601250), but zero homozygote observation in a general population database alone does not satisfy this VCEP-specific proband-scoring BS2 rule, and BRCA2-related FA is a rare recessive condition where absence of homozygotes in gnomAD is expected regardless of pathogenicity.
Rule
ENIGMA BRCA1/BRCA2 CSpec v1.2: BS2 — applied in absence of features of recessive (Fanconi Anemia) disease per Specifications Table 8 points system; BS2 = ≥4 points (Strong), 2 points (Moderate), 1 point (Supporting).
Evidence considered
gnomAD v2.1: 0 homozygotes observed (AN=232106).
gnomAD v4.1: 0 homozygotes observed (AN=1601250).
Still missing
No proband-level clinical history (chromosome breakage assay results, FA physical/pathology/laboratory features) available in the case bundle to apply the VCEP Table 8 points-based BS2 scoring.
Specifications_V1.2 Appendix H / Table 8 (raw docx/xlsx) was not extracted into the evidence bundle text for detailed point-value lookup.
BS4Not assessed: no quantitative non-segregation data was available for this variant.
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Reasoning
The ENIGMA BRCA1/BRCA2 VCEP specification defines BS4 as applicable and requires the same quantitative co-segregation Bayes LR framework as PP1, but in the non-segregation direction (Supporting LR<=0.48, Moderate LR<=0.23, Strong LR<=0.05, Very Strong LR<=0.00285; see Appendix I). This variant is a clearly loss-of-function frameshift (p.(Ile605TyrfsTer9)) with a 3-star ClinVar Expert Panel (ENIGMA) Pathogenic classification and 26+ concordant Pathogenic submissions with no conflicting or benign interpretations in ClinVar, which is inconsistent with a non-segregating variant; however, no quantitative family-level non-segregation LR data specific to this variant was located anywhere in the case bundle (HUMU-40-1557-s001.xlsx multifactorial table preview does not include a row for c.1813del, and no other segregation dataset or family study for this variant is present).
Rule
ENIGMA BRCA1/2 VCEP Specification v1.2, Table 1 (BS4): Bayes LR thresholds Supporting<=0.48:1, Moderate<=0.23:1, Strong<=0.05:1, Very Strong<=0.00285:1
Evidence considered
ENIGMA BRCA1/BRCA2 VCEP Specification v1.2, Table 1: BS4 requires quantitative co-segregation Bayes LR showing lack of segregation, with thresholds Supporting<=0.48, Moderate<=0.23, Strong<=0.05, Very Strong<=0.00285 (per Appendix I).
HUMU-40-1557-s001.xlsx (Parsons et al. 2019, PMID:31131967) SuppT1 multifactorial likelihood table contains a Segregation LR column, but no row for c.1813del/p.(Ile605TyrfsTer9) was found in the pre-extracted summary available in this case's vcep_materials.
ClinVar reports this variant as Pathogenic with 3-star Expert Panel (ENIGMA) review status and 26+ concordant Pathogenic clinical laboratory submissions with no benign/conflicting interpretations, which is not indicative of a non-segregating allele, though this is not itself a quantitative segregation analysis.
Still missing
No quantitative co-segregation LR data for NM_000059.4:c.1813del located in the ENIGMA multifactorial likelihood dataset available in this case's materials
No family segregation study reporting non-segregation in affected relatives was identified for this variant
Cannot rule out BS4 applicability without direct access to a segregation LR value for this specific allele
BP1Not assessed: insufficient evidence was available to evaluate this criterion.
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Reasoning
BP1 could not be assessed because its agent did not produce valid output.
Still missing
attempt 1: Hermes timed out after 200s and left no usable output_file
attempt 2: Hermes timed out after 200s and left no usable output_file
attempt 3: Hermes timed out after 200s and left no usable output_file
BP5Not assessed: no variant-specific clinical-history likelihood ratio was available.
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Reasoning
ENIGMA BRCA2 v1.2 BP5 mirrors PP4, using the same clinical-history LR model (Li 2020) in the opposite direction (Supporting LR<=0.48, Moderate<=0.23, Strong<=0.05, Very Strong<=0.00285), and is explicitly not applicable to co-occurrence with variants in other breast-ovarian cancer genes. No variant-specific clinical-history LR row for c.1813del was located in the bundle, and no observation of this variant co-occurring with a pathogenic variant in a different, unrelated-phenotype gene is documented. Given this is a well-established frameshift/PTC variant with unanimous expert-panel Pathogenic classification, a benign-direction LR would in any case be biologically implausible, but the required quantitative LR source data is absent from this bundle.
Rule
ENIGMA BRCA2 v1.2 BP5: clinical-history LR from Li 2020 multifactorial model. Supporting LR<=0.48, Moderate<=0.23, Strong<=0.05, Very Strong<=0.00285 (Specifications Table7/Appendix B). Not applicable for co-occurrence with unrelated breast-ovarian cancer genes.
Still missing
No variant-level clinical-history LR row for c.1813del located from PMID_31853058_BRCA2_clinical_history_LR.xlsx within the provided bundle
No alternative-phenotype-gene co-occurrence data present to consider (and BP5 explicitly excludes that scenario in ENIGMA v1.2 regardless)
Not applicable · 11· recorded as not applicableShow reasons ▾Hide reasons ▴PS2VCEPNot applicable: BRCA2 has no calibrated de novo-occurrence data, so this criterion cannot be used for this gene.
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Reasoning
The governing ClinGen ENIGMA BRCA1/BRCA2 VCEP specification (v1.2) explicitly marks PS2 as 'Not applicable' for BRCA1/BRCA2, with the stated rationale that BRCA1/2-related cancers occur relatively commonly and there is no information available to calibrate the predictive capacity of de novo occurrences for this gene/disease combination. No BRCA2-specific PS2 strength rules are provided (all strength levels listed as Not applicable in the specification). Additionally, the case bundle contains no proband-specific pedigree, trio, or parental-testing data (no family_history, pedigree, trio, or parentage-confirmation fields anywhere in review_manifest.json, case_summary.json, evidence.json, or the literature extracts) that would even support a generic ACMG PS2 assessment if the VCEP exclusion were disregarded.
VCEP rule
ENIGMA BRCA1/2 VCEP Specification v1.2, Table 1 (PS2): applicability = Not applicable for BRCA1/BRCA2
Evidence considered
ENIGMA BRCA1/BRCA2 VCEP Specification v1.2, Table 1: PS2 applicability = 'Not applicable'; instructionsToUse states 'BRCA1/2-related cancers occur relatively commonly. No information to calibrate the predictive capacity of de novo occurrences.' All PS2 strength_rules (Stand Alone, Very Strong, Strong, Moderate, Supporting) are listed as 'Not applicable' with empty rule text.
No proband/family de novo or trio testing information is present anywhere in the case evidence bundle (review_manifest.json, case_summary.json, evidence.json).
Still missing
No case-specific pedigree/trio data or confirmed maternity+paternity information available in this case bundle
VCEP explicitly excludes PS2 for this gene regardless of de novo data availability
PS3N/ANot applicable: functional-assay evidence for BRCA2 applies only to missense or synonymous variants, not this frameshift.
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Reasoning
NM_000059.4:c.1813del (p.Ile605TyrfsTer9) is a frameshift/null variant assessed under PVS1, not PS3. The ENIGMA BRCA1/2 VCEP specification v1.2 (cspec) scopes PS3/BS3 code application to functional-assay data via Specifications Table 9, which is explicitly restricted to missense and synonymous variant types (per index_guidance/vcep_materials use notes for Specifications_Table9_V1.2). No calibrated protein-, mRNA-, or HDR-based functional assay data exists in that table for this frameshift deletion, and no variant-specific functional study for c.1813del/p.Ile605TyrfsTer9 was found in the case bundle. The only functional-theme literature retrieved (PMID:10570174, PMID:11239455, PMID:22193408, PMID:24312913, PMID:20878484) discusses general BRCA2 biology/mechanism (cytoplasmic localization of truncated BRCA2, homology-directed repair role) without mentioning this specific variant, so per grounding rules these cannot be cited as variant-specific functional evidence. HUMU-40-1557-s001 SuppT9 lists a functionally-characterized proband with c.1813dupA (p.Ile605Asnfs*11) -- a different variant (duplication, not deletion, different frameshift) -- and is not an exact match for this variant. PS3 is therefore not applicable for this variant under the ENIGMA framework's functional-assay pathway; pathogenicity for this null variant is instead addressed by PVS1 in the loss-of-function group.
Evidence considered
ENIGMA BRCA1/2 VCEP Specifications v1.2 (cspec) defines PS3 rule strength via Specifications Table 9, scoped in vcep_materials/index_guidance to missense and synonymous variant types only.
Specifications_Table9_V1.2_2024-11-18.xlsx (Dace & Findlay interim report) contains only missense/synonymous/canonical-splice function scores for BRCA2 exons; no entry corresponds to c.1813del.
HUMU-40-1557-s001.xlsx SuppT9 BRCA2 Fanconi Anemia table lists c.1813dupA p.(Ile605Asnfs*11) with PMID:15070707 and PMID:21548015, a different variant (duplication vs. deletion, distinct frameshift/stop position) from NM_000059.4:c.1813del, therefore not usable as PS3 evidence for this variant.
PMID:10570174, PMID:11239455, PMID:22193408, PMID:24312913, and PMID:20878484 (OncoKB functional-theme literature) discuss general BRCA2 protein function/mechanism (truncated-protein cytoplasmic localization, homologous-recombination role) without mentioning c.1813del specifically, failing the strict variant-grounding requirement for PS3 citation.
Still missing
No variant-specific functional assay (protein, mRNA, or HDR) data for NM_000059.4:c.1813del/p.Ile605TyrfsTer9 was found in gene-VCEP Specifications Table 9, HUMU-40-1557-s001 SuppT4 (functional assay cross-reference), or the literature pass.
ENIGMA VCEP restricts PS3/BS3 Table 9 lookups to missense/synonymous types; framework has no functional-assay pathway defined for frameshift/null variants of this type.
PM4VCEPNot applicable: this is a frameshift deletion, not an in-frame length change or stop-loss variant.
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Reasoning
PM4 addresses protein length changes from in-frame insertions/deletions or stop-loss variants in a non-repeat region. NM_000059.4:c.1813del is a frameshift deletion producing a premature termination codon (p.Ile605TyrfsTer9), not an in-frame length change or stop-loss. Its consequence is already captured under PVS1 (null variant/NMD-predicted truncation); PM4 does not apply to frameshift variants and would double-count the same loss-of-function mechanism if applied.
VCEP rule
PM4 applies only to in-frame insertion/deletion or stop-loss variants causing a protein length change outside a repetitive region; not applicable to frameshift/null variants already assessed under PVS1.
Evidence considered
pvs1_variant_assessment.json: consequence_class = 'frameshift', variant_bucket = 'frameshift' — confirms this is not an in-frame indel or stop-loss variant, so PM4 (protein length change) criteria do not apply.
Sources
pvs1_variant_assessment
PM6VCEPNot applicable: BRCA2 has no calibrated de novo-occurrence data, and no unconfirmed-parentage information was available.
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Reasoning
The governing ClinGen ENIGMA BRCA1/BRCA2 VCEP specification (v1.2) explicitly marks PM6 (assumed de novo without confirmed parentage) as 'Not applicable' for BRCA1/BRCA2, citing the same rationale as PS2: BRCA1/2-related cancers occur relatively commonly, so there is no information to calibrate the predictive capacity of de novo occurrences in this gene. No BRCA2-specific PM6 strength rules are defined. The case bundle also contains no proband-specific assumed-de-novo or unconfirmed-parentage information.
VCEP rule
ENIGMA BRCA1/2 VCEP Specification v1.2, Table 1 (PM6): applicability = Not applicable for BRCA1/BRCA2
Evidence considered
ENIGMA BRCA1/BRCA2 VCEP Specification v1.2, Table 1: PM6 applicability = 'Not Applicable', same instructionsToUse rationale as PS2 (BRCA1/2-related cancers occur relatively commonly; no information to calibrate predictive capacity of de novo occurrences).
No proband/family assumed-de-novo information is present anywhere in the case evidence bundle.
Still missing
No case-specific assumed de novo / unconfirmed parentage data available in this case bundle
VCEP explicitly excludes PM6 for this gene regardless of assumed de novo data availability
PP3N/ANot applicable: this criterion covers missense, splicing, or in-frame variants, and does not apply to this frameshift deletion.
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Reasoning
NM_000059.4:c.1813del is a frameshift deletion (p.(Ile605TyrfsTer9)), not a missense, in-frame indel, silent, or intronic variant. The governing ENIGMA BRCA1/2 VCEP specification (v1.2) restricts its PP3 bioinformatic-evidence rule (Figure 1A / Table 1) to: (1) missense or in-frame insertion/deletion/delins variants inside a defined clinically important functional domain with BayesDel no-AF score >=0.30, or (2) predicted splicing impact (SpliceAI >=0.2) for silent, missense/in-frame, or intronic variants outside the donor/acceptor +/-1,2 positions. A frameshift (out-of-frame) deletion falls outside all of these variant classes and is instead evaluated under the PVS1 null-variant pathway per the same specification. SpliceAI was queried for completeness and shows no meaningful splice-altering signal (DS_AG=0.0, DS_AL=0.0, DS_DG=0.018, DS_DL=0.014; max delta=0.018), which is far below the VCEP's PP3 splicing threshold of >=0.2 in any case, reinforcing that PP3 is not met via the splice-impact sub-path either even if it were considered applicable.
Rule
ENIGMA BRCA1/2 VCEP v1.2 PP3 rule applies only to missense/in-frame indel (functional domain + BayesDel no-AF >=0.30) or silent/missense/in-frame/intronic-outside-consensus-site (SpliceAI >=0.2) variant classes; frameshift out-of-frame deletions are excluded and handled via PVS1.
Evidence considered
ENIGMA BRCA1/2 VCEP Specifications v1.2 PP3 rule text: '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 no-AF score >=0.30) ... Apply PP3 for predicted splicing (SpliceAI >=0.2) for silent, missense/in-frame ... and for intronic variants outside of donor and acceptor 1,2 sites.'
pvs1_variant_assessment.json classifies NM_000059.4:c.1813del as consequence_class=frameshift, variant_bucket=frameshift, canonical_splice_consensus=false, and notes that for canonical splice variants PP3 should not be stacked with PVS1 evidence for the same splice-effect prediction, implying the bioinformatic PP3/BP4/BP7 pathway is reserved for missense/silent/intronic classes, not frameshift null variants.
SpliceAI Lookup scores for this variant (source_registry key spliceai): DS_AG=0.0, DS_AL=0.0, DS_DG=0.018, DS_DL=0.014, max delta=0.018 — no significant predicted splice impact, well below any PP3/BP4 threshold in the VCEP framework.
BS3N/ANot applicable: benign functional-assay evidence for BRCA2 applies only to missense or synonymous variants, not this frameshift.
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Reasoning
Same scope restriction as PS3: the ENIGMA BRCA1/2 VCEP specification v1.2 confines BS3 functional-assay code application to Specifications Table 9, which covers only missense and synonymous variant types. NM_000059.4:c.1813del is a frameshift/null variant (p.Ile605TyrfsTer9) and has no benign functional-assay data (no calibrated assay showing no damaging effect) in Table 9, SupplementaryTables_V1.2 SuppT4/ST11 (all restricted to missense/synonymous entries), or the literature pass. No qualifying evidence exists for BS3 in either direction for this variant type.
Evidence considered
ENIGMA BRCA1/2 VCEP Specifications v1.2 (cspec) BS3 rule references Specifications Table 9 for calibrated assay code recommendations, explicitly scoped to missense and synonymous types only.
SupplementaryTables_V1.2_2024-11-18.xlsx ST4 (Fxn assay results) and ST11 (Dataset Bioinf) contain only BRCA1 missense/synonymous variant rows in the extracted sample; no BRCA2 c.1813del entry present.
No published functional study (protein-, mRNA-, or HDR-based) reporting a non-damaging/no-functional-impact result for NM_000059.4:c.1813del was identified in the case evidence bundle.
Still missing
No functional assay data of any kind (damaging or benign) exists for this specific frameshift deletion in the reviewed gene-VCEP tables or literature.
ENIGMA VCEP has no defined BS3 functional-assay pathway for frameshift/null variants of this class.
BP2VCEPNot applicable: this criterion is not used for BRCA2 under the governing expert panel specification.
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Reasoning
The ENIGMA BRCA1/BRCA2 v1.2 VCEP specification explicitly designates BP2 as 'Not Applicable' for BRCA2 variant classification (case_summary.json cspec criteria list). The generic ACMG BP2 rule (observed in trans with a pathogenic variant for a fully penetrant dominant disorder, or in cis with a pathogenic variant in any inheritance pattern) is superseded by the VCEP's gene-specific PM3/BS2 point-based Fanconi Anemia co-occurrence framework, which supersedes standard BP2/PM3 logic for this gene. Since a governing VCEP specification exists and explicitly marks this criterion not applicable, the generic ACMG BP2 rule is not used as a fallback.
VCEP rule
ENIGMA BRCA1/BRCA2 VCEP v1.2 - BP2 marked Not Applicable
Evidence considered
ENIGMA BRCA1/BRCA2 v1.2 VCEP specification (cspec) lists BP2 with applicability = 'Not Applicable' for BRCA2, superseded by the gene's dedicated PM3 (FA co-occurrence)/BS2 (absence of FA phenotype) point-based framework.
BP3VCEPNot applicable: this criterion is not used for BRCA2, and also does not fit a frameshift deletion.
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Reasoning
BP3 addresses in-frame insertions/deletions in a repetitive region with no known functional impact. The ENIGMA BRCA2 CSPEC (v1.2) explicitly designates BP3 as Not Applicable for BRCA2 in this framework. Independently, this variant is a frameshift deletion, not an in-frame indel, so BP3 would not apply on variant-consequence grounds either.
VCEP rule
BP3: In-frame indel in a repetitive region without known function — marked Not Applicable by the ENIGMA BRCA2 VCEP specification (v1.2) and not applicable to this frameshift variant on structural grounds.
Evidence considered
cspec (ENIGMA BRCA2 Specification v1.2): BP3 listed with applicability 'Not Applicable' for the BRCA2 gene-specific framework.
pvs1_variant_assessment.json: consequence_class = 'frameshift', confirming the variant is not an in-frame insertion/deletion, so BP3's repeat-region in-frame-indel criterion is not met on structural grounds either.
BP4N/ANot applicable: this criterion covers missense, splicing, or in-frame variants, and does not apply to this frameshift deletion.
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Reasoning
As with PP3, the ENIGMA VCEP's BP4 rule (Figure 1A / Table 1) applies only to missense/in-frame indel variants inside a functional domain with no predicted protein or splicing impact (BayesDel no-AF <=0.18 AND SpliceAI <=0.1), silent variants inside a functional domain with SpliceAI <=0.1, or intronic variants outside the native donor/acceptor sites with SpliceAI <=0.1. c.1813del is a frameshift (out-of-frame) deletion and does not belong to any of these variant classes, so the BP4 bioinformatic-evidence rule does not apply; the variant is instead assessed as a null variant under PVS1. SpliceAI itself shows no splice impact (max delta=0.018, well under the 0.1 threshold), but this does not change applicability since the variant class is out of scope for BP4 regardless of the score.
Rule
ENIGMA BRCA1/2 VCEP v1.2 BP4 rule applies only to missense/in-frame indel (functional domain + BayesDel no-AF <=0.18 AND SpliceAI <=0.1), silent-in-domain (SpliceAI <=0.1), or intronic-outside-consensus-site (SpliceAI <=0.1) variant classes; frameshift out-of-frame deletions are excluded.
Evidence considered
ENIGMA BRCA1/2 VCEP Specifications v1.2 BP4 rule text: 'Missense or in-frame insertion, deletion or delins variants inside a (potentially) clinically important functional domain, and no predicted impact via protein change or splicing (BayesDel no-AF score <=0.18 AND SpliceAI <=0.1). Silent variant inside a (potentially) clinically important functional domain, if no predicted impact via splicing (SpliceAI <=0.1). Intronic variants outside of the native donor and acceptor splice sites ... AND no predicted impact via splicing (SpliceAI <=0.1).'
pvs1_variant_assessment.json: variant_bucket=frameshift, consequence_class=frameshift, apply_generic_pvs1_framework=true, suggested_default_strength=PVS1 — confirming this variant is handled by the null-variant/PVS1 pathway rather than the bioinformatic PP3/BP4/BP7 pathway.
SpliceAI Lookup (source_registry key spliceai) max delta score = 0.018, DS_AG=0.0, DS_AL=0.0, DS_DG=0.018, DS_DL=0.014 — no splice signal, but not the deciding factor for applicability here since the variant class itself is out of scope.
BP6VCEPNot applicable: no benign or likely-benign expert-panel classification exists for this variant in ClinVar.
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Reasoning
No Benign/Likely benign ClinVar expert-panel classification exists for this exact variant. ClinVar shows unanimous Pathogenic classification (26 single-submitter labs, 1 lab, and the ENIGMA expert panel), with no benign-direction submissions at any tier. BP6 cannot apply.
ClinVar VCV000037763 shows exclusively Pathogenic submissions for c.1813del across all 34 submitters including the ENIGMA expert panel; no Benign/Likely benign classification of any tier exists to trigger BP6.
BP7N/ANot applicable: this criterion covers intronic or synonymous variants, and does not apply to this frameshift deletion.
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Reasoning
BP7 under the ENIGMA VCEP specification is defined specifically for intronic and silent (synonymous) variants (plus missense/in-frame variants outside a functional domain when qualified by functional RNA data), contingent on BP4 being met and, at Strong strength, on mRNA functional assay data. c.1813del is a frameshift-causing deletion, not a synonymous or intronic variant, so BP7 does not apply to this variant class at all.
Rule
ENIGMA BRCA1/2 VCEP v1.2 BP7 rule applies only to synonymous/silent and intronic variant classes (or, for BP7_Strong, missense/in-frame outside a functional domain with supporting mRNA data); frameshift out-of-frame deletions are excluded.
Evidence considered
ENIGMA BRCA1/2 VCEP Specifications v1.2 BP7 rule text: 'Silent variant inside a (potentially) clinically important functional domain, IF BP4 met. Intronic variants located outside conserved donor or acceptor motif positions ... IF BP4 met,' and the Strong-strength variant applies to intronic, silent, or out-of-domain missense/in-frame variants with mRNA functional data.
pvs1_variant_assessment.json confirms consequence_class=frameshift for c.1813del, which is neither a synonymous (silent) coding change nor an intronic variant, so it falls outside BP7's defined variant scope entirely.
AF 9.4e-06 · 15 / 1,601,250 alleles · 0 hom · FAF 1.4e-05
Admixed American3 / 56,988
5.3e-05
East Asian2 / 44,798
4.5e-05
South Asian3 / 88,210
3.4e-05
European (non-Finnish)7 / 1,175,924
6e-06
0 alternate alleles recorded in 6 other groups: Remaining individuals, European (Finnish), Amish, Middle Eastern, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 3.4e-05 · 8 / 232,106 alleles · 0 hom · FAF 3e-05
South Asian3 / 26,880
0.00011
Admixed American3 / 30,762
9.8e-05
European (non-Finnish)2 / 106,112
1.9e-05
0 alternate alleles recorded in 5 other groups: African/African American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 9.36768e-06; MAF= 0.00094%, 15/1601250 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 5.26427e-05; MAF= 0.00526%, 3/56988 alleles, homozygotes = 0); grpmax FAF= 1.397e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.4467e-05; MAF= 0.00345%, 8/232106 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000111607; MAF= 0.01116%, 3/26880 alleles, homozygotes = 0); grpmax FAF= 2.955e-05.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
SpliceAI acceptor lossat -307 bp
0.000
SpliceAI acceptor gainat +0 bp
0.000
SpliceAI donor lossat +104 bp
0.014
SpliceAI donor gainat -73 bp
0.018
Pangolin splice lossmagnitude shown
-0.270
Pangolin splice gain
0.007
Other predictors
REVEL
Not available
BayesDel
Not available
How the predictions were used
PP3N/ANot applicable: this criterion covers missense, splicing, or in-frame variants, and does not apply to this frameshift deletion.
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Reasoning
NM_000059.4:c.1813del is a frameshift deletion (p.(Ile605TyrfsTer9)), not a missense, in-frame indel, silent, or intronic variant. The governing ENIGMA BRCA1/2 VCEP specification (v1.2) restricts its PP3 bioinformatic-evidence rule (Figure 1A / Table 1) to: (1) missense or in-frame insertion/deletion/delins variants inside a defined clinically important functional domain with BayesDel no-AF score >=0.30, or (2) predicted splicing impact (SpliceAI >=0.2) for silent, missense/in-frame, or intronic variants outside the donor/acceptor +/-1,2 positions. A frameshift (out-of-frame) deletion falls outside all of these variant classes and is instead evaluated under the PVS1 null-variant pathway per the same specification. SpliceAI was queried for completeness and shows no meaningful splice-altering signal (DS_AG=0.0, DS_AL=0.0, DS_DG=0.018, DS_DL=0.014; max delta=0.018), which is far below the VCEP's PP3 splicing threshold of >=0.2 in any case, reinforcing that PP3 is not met via the splice-impact sub-path either even if it were considered applicable.
Rule
ENIGMA BRCA1/2 VCEP v1.2 PP3 rule applies only to missense/in-frame indel (functional domain + BayesDel no-AF >=0.30) or silent/missense/in-frame/intronic-outside-consensus-site (SpliceAI >=0.2) variant classes; frameshift out-of-frame deletions are excluded and handled via PVS1.
Evidence considered
ENIGMA BRCA1/2 VCEP Specifications v1.2 PP3 rule text: '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 no-AF score >=0.30) ... Apply PP3 for predicted splicing (SpliceAI >=0.2) for silent, missense/in-frame ... and for intronic variants outside of donor and acceptor 1,2 sites.'
pvs1_variant_assessment.json classifies NM_000059.4:c.1813del as consequence_class=frameshift, variant_bucket=frameshift, canonical_splice_consensus=false, and notes that for canonical splice variants PP3 should not be stacked with PVS1 evidence for the same splice-effect prediction, implying the bioinformatic PP3/BP4/BP7 pathway is reserved for missense/silent/intronic classes, not frameshift null variants.
SpliceAI Lookup scores for this variant (source_registry key spliceai): DS_AG=0.0, DS_AL=0.0, DS_DG=0.018, DS_DL=0.014, max delta=0.018 — no significant predicted splice impact, well below any PP3/BP4 threshold in the VCEP framework.
BP4N/ANot applicable: this criterion covers missense, splicing, or in-frame variants, and does not apply to this frameshift deletion.
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Reasoning
As with PP3, the ENIGMA VCEP's BP4 rule (Figure 1A / Table 1) applies only to missense/in-frame indel variants inside a functional domain with no predicted protein or splicing impact (BayesDel no-AF <=0.18 AND SpliceAI <=0.1), silent variants inside a functional domain with SpliceAI <=0.1, or intronic variants outside the native donor/acceptor sites with SpliceAI <=0.1. c.1813del is a frameshift (out-of-frame) deletion and does not belong to any of these variant classes, so the BP4 bioinformatic-evidence rule does not apply; the variant is instead assessed as a null variant under PVS1. SpliceAI itself shows no splice impact (max delta=0.018, well under the 0.1 threshold), but this does not change applicability since the variant class is out of scope for BP4 regardless of the score.
Rule
ENIGMA BRCA1/2 VCEP v1.2 BP4 rule applies only to missense/in-frame indel (functional domain + BayesDel no-AF <=0.18 AND SpliceAI <=0.1), silent-in-domain (SpliceAI <=0.1), or intronic-outside-consensus-site (SpliceAI <=0.1) variant classes; frameshift out-of-frame deletions are excluded.
Evidence considered
ENIGMA BRCA1/2 VCEP Specifications v1.2 BP4 rule text: 'Missense or in-frame insertion, deletion or delins variants inside a (potentially) clinically important functional domain, and no predicted impact via protein change or splicing (BayesDel no-AF score <=0.18 AND SpliceAI <=0.1). Silent variant inside a (potentially) clinically important functional domain, if no predicted impact via splicing (SpliceAI <=0.1). Intronic variants outside of the native donor and acceptor splice sites ... AND no predicted impact via splicing (SpliceAI <=0.1).'
pvs1_variant_assessment.json: variant_bucket=frameshift, consequence_class=frameshift, apply_generic_pvs1_framework=true, suggested_default_strength=PVS1 — confirming this variant is handled by the null-variant/PVS1 pathway rather than the bioinformatic PP3/BP4/BP7 pathway.
SpliceAI Lookup (source_registry key spliceai) max delta score = 0.018, DS_AG=0.0, DS_AL=0.0, DS_DG=0.018, DS_DL=0.014 — no splice signal, but not the deciding factor for applicability here since the variant class itself is out of scope.
BP7N/ANot applicable: this criterion covers intronic or synonymous variants, and does not apply to this frameshift deletion.
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Reasoning
BP7 under the ENIGMA VCEP specification is defined specifically for intronic and silent (synonymous) variants (plus missense/in-frame variants outside a functional domain when qualified by functional RNA data), contingent on BP4 being met and, at Strong strength, on mRNA functional assay data. c.1813del is a frameshift-causing deletion, not a synonymous or intronic variant, so BP7 does not apply to this variant class at all.
Rule
ENIGMA BRCA1/2 VCEP v1.2 BP7 rule applies only to synonymous/silent and intronic variant classes (or, for BP7_Strong, missense/in-frame outside a functional domain with supporting mRNA data); frameshift out-of-frame deletions are excluded.
Evidence considered
ENIGMA BRCA1/2 VCEP Specifications v1.2 BP7 rule text: 'Silent variant inside a (potentially) clinically important functional domain, IF BP4 met. Intronic variants located outside conserved donor or acceptor motif positions ... IF BP4 met,' and the Strong-strength variant applies to intronic, silent, or out-of-domain missense/in-frame variants with mRNA functional data.
pvs1_variant_assessment.json confirms consequence_class=frameshift for c.1813del, which is neither a synonymous (silent) coding change nor an intronic variant, so it falls outside BP7's defined variant scope entirely.
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).
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.
Comprehensive analysis of 989 patients with breast or ovarian cancer provides BRCA1 and BRCA2 mutation profiles and frequencies for the German population.
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 9.36768e-06; MAF= 0.00094%, 15/1601250 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 5.26427e-05; MAF= 0.00526%, 3/56988 alleles, homozygotes = 0); grpmax FAF= 1.397e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.4467e-05; MAF= 0.00345%, 8/232106 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000111607; MAF= 0.01116%, 3/26880 alleles, homozygotes = 0); grpmax FAF= 2.955e-05.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Pathogenic (26 clinical laboratories) and as pathogenic (1 clinical laboratory) and as Pathogenic by Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) (expert panel). (ClinVarID = 37763)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).
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 previously been reported in somatic cancers (COSMIC; COSV66449038, n = 15 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
This variant was interpreted by pipeline 7.2.0.
The current version is 11.0.07.
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