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BRCA27141_7147dupPathogenic
Print report
Variant interpretation report

BRCA2 7141_7147dup

NM_000059.4:7141_7147dup Unknown View identifiers
Classification
Pathogenic

Variant description:

No variant summary was recorded for this case.

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

Pathogenic.A pathogenic classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

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

Met, very strong: exon-15 frameshift p.(Tyr2383SerfsTer11) truncates the predicted product at residue 2393 of 3419 and is expected to undergo NMD.

PM5Strong
PM5 · strong

Met, Strong: ENIGMA Table 4 assigns PM5_Strong (PTC) to BRCA2 exon 14, where c.7141_7147dup creates p.(Tyr2383SerfsTer11).

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 combination rule.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

No screenshot for this evidence
Population frequency
Not recorded

gnomAD v4.1 allele counts were not recorded for this variant.

No listed criterion applied gnomAD-Canada ↗
No screenshot for this evidence
Computational predictions
Not recorded

No SpliceAI or REVEL score is recorded in the fields used for this tile.

No listed criterion applied
No screenshot for this evidence
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
No screenshot for this evidence
Functional evidence
Not recorded

No standalone functional evidence summary is recorded in evidence_summary.functional.

No listed criterion applied OncoKB ↗
Somatic evidence
No matching record reported

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

Context only COSMIC ↗
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: 2 met · 0 not met · 13 not assessed · 13 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

The ENIGMA BRCA2-specific framework supports full PVS1 for this exon-15 frameshift premature-termination variant; PM4 and BP3 are explicitly not applicable under the VCEP specification.

The governing ENIGMA BRCA2 specification was applied first.

The only applicable codon/residue/domain criterion is PM5_Strong (PTC), pre-assigned by Table 4 for exon 14; PS1, PM1, PP2, and BP1 are not applicable to this frameshift duplication.

All three requested criteria are not_applicable because NM_000059.4:c.7141_7147dup is an exonic frameshift duplication, predicted as p.(Tyr2383SerfsTer11); no PP3, BP4, or BP7 predictor assessment was performed.

Met · 2

PVS1 Very strongMet, very strong: exon-15 frameshift p.(Tyr2383SerfsTer11) truncates the predicted product at residue 2393 of 3419 and is expected to undergo NMD. Details ▾Hide ▴
Reasoning

NM_000059.4:c.7141_7147dup is a 7-bp duplication in BRCA2 exon 15 that creates a frameshift, p.(Tyr2383SerfsTer11), truncating the normal 3419-aa product at predicted residue 2393. The predicted termination codon is well upstream of the terminal exon and is expected to trigger nonsense-mediated decay, eliminating the downstream DNA-binding region and other essential C-terminal sequence. BRCA2 loss of function is an established disease mechanism in the ENIGMA framework. The governing ENIGMA Table 4 exon-15 PTC row assigns full PVS1, and its exon-15 coding duplication entry also assigns PVS1; no named downgrade rule applies.

Rule
ENIGMA BRCA2 v1.2 Table 4: exon 15 predicted termination codon and coding duplication categories are assigned PVS1; full-strength PVS1 is reported as very strong.
Evidence considered
  • The normalized consequence is NM_000059.4:c.7141_7147dup, a duplication producing NM_000059.4(NP_000050.3):p.(Tyr2383SerfsTer11); the predicted protein ends at residue 2393 while the original ends at residue 3419.
  • ENIGMA BRCA2 specification v1.2 states that null variants including nonsense and frameshift variants receive PVS1 according to the exon-organized PVS1 flowchart and Table 4.
  • ENIGMA Table 4 lists BRCA2 exon 15 PTC variants as PVS1 and lists the exon-15 coding duplication category as PVS1; the variant lies within the exon-15 coding interval c.6938-c.7435.
  • The predicted termination is far upstream of the terminal exon and removes the downstream DNA-binding region, supporting loss of transcript/product function; no VCEP-specific downgrade rule is present for this variant.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18vcep_specifications_table4_v1_2_2024_11_18
PM5 StrongMet, Strong: ENIGMA Table 4 assigns PM5_Strong (PTC) to BRCA2 exon 14, where c.7141_7147dup creates p.(Tyr2383SerfsTer11). Details ▾Hide ▴
Reasoning

The variant is a coding duplication that produces a predicted protein termination codon, p.(Tyr2383SerfsTer11), with the altered nucleotide range c.7141_7147 located in BRCA2 exon 14 (c.7008-c.7435). ENIGMA repurposes PM5 for genomic PTC variants and its Table 4 assigns PM5_Strong (PTC) to exon 14, where a different proven pathogenic PTC has previously been observed. This governing pre-assigned code takes precedence over generic classic same-residue missense PM5 logic.

Rule
For BRCA2, PM5 is applied only to genomic PTC changes; the weight is determined by the exon containing the nucleotide change. Table 4 assigns PM5_Strong (PTC) for exon 14.
Evidence considered
  • Mutalyzer normalization gives NM_000059.4:c.7141_7147dup and predicts p.(Tyr2383SerfsTer11), a premature termination after a frameshift.
  • Specifications_Table4_V1.2_2024-11-18.xlsx.txt places BRCA2 c.7008-c.7435 in exon 14 and assigns the exon 14 PTC row PM5_Strong (PTC).
  • The ENIGMA specification repurposes PM5 for PTC variants and directs use of exon-specific Table 4 weights; this is not classic same-residue missense PM5.
Sources
cspec ↗vcep_specifications_table4_v1_2_2024_11_18

Not assessed · 13 · no assessment recorded

PS3 Not assessed: no variant-specific calibrated functional assay result for c.7141_7147dup was found in the governing ENIGMA sources or case evidence. Details ▾Hide ▴
Reasoning

The governing ENIGMA BRCA2 VCEP specification requires PS3 only for well-established calibrated functional studies showing a damaging protein effect, or combined mRNA-and-protein effect; mRNA-only evidence is handled under the alternative PVS1 (RNA) framework. The variant NM_000059.4:c.7141_7147dup was searched in Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, Specifications_Table9_V1.2_2024-11-18.xlsx.txt, and HUMU-40-1557-s001.xlsx.txt, with no variant-specific functional-assay entry found. The case-evidence bundle contains no functional assay finding or relevant extracted publication for this variant. Therefore, PS3 cannot be assigned.

Rule
Well-established in vitro or in vivo functional studies supportive of a damaging effect; apply PS3 for assays measuring protein effect alone or mRNA and protein combined. Use the calibrated assay recommendations in ENIGMA Specifications Table 9. mRNA-only damaging evidence is handled under PVS1 (RNA), not PS3.
Evidence considered
  • The ENIGMA BRCA2 VCEP specification states that PS3 functional-assay evidence applies to well-established in vitro or in vivo studies measuring protein function, or mRNA and protein together, and directs calibrated assay lookups to Table 9.
  • The ENIGMA Table 9 text states that its listed calibrated assay results provide PS3/BS3 code recommendations and that additional published assays require review under the VCEP functional-assay recommendations.
  • Searches of Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, Specifications_Table9_V1.2_2024-11-18.xlsx.txt, and HUMU-40-1557-s001.xlsx.txt found no entry for NM_000059.4:c.7141_7147dup or an equivalent notation.
  • The case-evidence bundle reports no PMIDs and contains no variant-specific functional assay finding for this case.
Still missing
  • No entry for NM_000059.4:c.7141_7147dup or an equivalent notation was found in Specifications_Table9_V1.2_2024-11-18.xlsx.txt.
  • No variant-specific functional evidence was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No variant-specific functional evidence was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No variant-specific functional evidence was found in HUMU-40-1557-s001.xlsx.txt.
  • No case-level functional assay result or relevant paper extraction was present in the functional evidence bundle.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18vcep_specifications_table9_v1_2_2024_11_18vcep_humu_40_1557_s001
PS4 Not assessed: no variant-specific case-control p-value, OR, or confidence interval was available to evaluate the PS4 requirements p-value <=0.05 and OR >=4. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 specification requires PS4 case-control evidence with p-value <=0.05, OR >=4, and a lower confidence interval excluding 2.0. No case-control dataset, odds ratio, confidence interval, or p-value for NM_000059.4:c.7141_7147dup was present in the case evidence. The governing SupplementaryTables_V1.2_2024-11-18.xlsx file was searched for 7141_7147dup, c.7141_7147dup, 7141, and 7147 with no variant-specific entry found; its full text is documented as unavailable for reliable complete review. Therefore PS4 cannot be assessed, rather than treated as absent evidence.

Rule
Case-control studies; p-value <=0.05 and OR >=4, with the lower confidence interval excluding 2.0.
Evidence considered
  • The ENIGMA BRCA2 specification states: "Case-control studies; p-value <=0.05 and OR >=4 (lower confidence interval excludes 2.0)."
  • The case evidence records no case-control results for NM_000059.4:c.7141_7147dup.
  • SupplementaryTables_V1.2_2024-11-18.xlsx was searched for the variant forms 7141_7147dup, c.7141_7147dup, 7141, and 7147; no variant-specific entry was found, and the declared full text is unavailable for reliable complete review.
Still missing
  • No variant-specific case-control counts, p-value, odds ratio, or confidence interval were available.
  • No entry for NM_000059.4:c.7141_7147dup was found when searching SupplementaryTables_V1.2_2024-11-18.xlsx; the full text is unavailable for reliable complete review.
Sources
cspec ↗vcep_supplementarytables_v1_2_2024_11_18
PM3 Not assessed: no Fanconi-anemia phenotype, chromosome-breakage result, or pathogenic BRCA2 co-occurring variant with phase information is documented for this duplication. Details ▾Hide ▴
Reasoning

The governing ENIGMA BRCA2 VCEP specification applies PM3 only to a patient with a phenotype consistent with BRCA1- or BRCA2-related Fanconi anemia and a co-occurrent pathogenic or likely pathogenic variant in the same gene. PM3 points require documented chromosome-breakage evidence and qualifying clinical features, or at least two qualifying clinical features from at least two categories when chromosome-breakage results are unknown; 1 point is Supporting, 2 points are Moderate, and at least 4 points are Strong. The available case evidence contains no affected-proband phenotype, chromosome-breakage result, second BRCA2 pathogenic/likely pathogenic variant, phase information, or co-occurrence observation for NM_000059.4:c.7141_7147dup, so PM3 cannot be assigned. The complete governing file was searched for c.7141_7147dup, 7141_7147dup, and the normalized protein consequence p.(Tyr2383SerfsTer11), with no variant-specific entry found.

Rule
Apply PM3 for a patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi anemia and co-occurrent pathogenic or likely pathogenic variants in the same gene; PM3 Supporting = 1 point, PM3 = 2 points, and PM3 Strong = at least 4 points.
Evidence considered
  • The ENIGMA BRCA2 VCEP specification states that PM3 applies to a patient with a phenotype consistent with BRCA1- or BRCA2-related Fanconi anemia and a co-occurrent pathogenic or likely pathogenic variant in the same gene.
  • The specification requires increased chromosome breakage plus at least one qualifying clinical feature, or at least two qualifying clinical features from at least two categories when chromosome-breakage results are unknown.
  • The specification assigns PM3 Supporting for 1 point, PM3 for 2 points, and PM3 Strong for at least 4 points across unrelated individuals.
  • No case-level phase, co-occurrence, affected-proband, or Fanconi-anemia evidence is available for this variant.
Still missing
  • No affected-proband Fanconi-anemia phenotype or qualifying clinical features are documented.
  • No chromosome-breakage result using DEB, MMC, or spontaneous-breakage assessment is documented.
  • No co-occurring BRCA2 pathogenic or likely pathogenic variant is documented.
  • No phase information establishes a pathogenic or likely pathogenic BRCA2 variant in trans or a homozygous state.
  • No variant-specific entry was found after searching Specifications_V1.2_2024-11-18.docx.txt for c.7141_7147dup, 7141_7147dup, and p.(Tyr2383SerfsTer11).
Sources
vcep_specifications_v1_2_2024_11_18
PP1 Not assessed: no affected-relative segregation data or quantitative likelihood ratio was available to reach the ENIGMA PP1 threshold of LR ≥2.08:1. Details ▾Hide ▴
Reasoning

No affected relatives, pedigree, parental testing, phase information, meioses, or quantitative co-segregation likelihood ratio was documented for NM_000059.4:c.7141_7147dup. Under ENIGMA v1.2, PP1 requires co-segregation in multiple affected family members measured quantitatively; without those data, no PP1 strength can be assigned.

Rule
Apply weight as per Bayes Score: PP1 - LR ≥2.08:1; PP1_Moderate - LR ≥4.3:1; PP1_Strong - LR ≥18.7:1; PP1_Very Strong - LR ≥350:1. Co-segregation must involve multiple affected family members and be measured quantitatively.
Evidence considered
  • ENIGMA v1.2 specifies PP1 as quantitative co-segregation with disease in multiple affected family members, with PP1 Supporting at LR ≥2.08:1, PP1 Moderate at LR ≥4.3:1, PP1 Strong at LR ≥18.7:1, and PP1 Very Strong at LR ≥350:1.
  • The case evidence records no pedigree, affected relatives, parental testing, phase, meioses, or segregation LR for NM_000059.4:c.7141_7147dup.
  • The searched VCEP variant tables did not provide a usable variant-specific segregation result.
Still missing
  • No affected-relative pedigree or tested-family-member data were available for NM_000059.4:c.7141_7147dup.
  • No quantitative co-segregation LR, meiosis count, or phase information was available.
  • No entry for this variant was found when searching Specifications_Table4_V1.2_2024-11-18.xlsx; this table is not applicable to PP1.
  • No entry for this variant was found when searching HUMU-40-1557-s001.xlsx; the file contains no usable segregation result for this variant.
  • SupplementaryTables_V1.2_2024-11-18.xlsx full text was unavailable for the requested lookup, so it could not be independently searched for a variant-specific BS4/PS4 table entry.
Sources
cspec ↗
PP4 Not assessed: no variant-specific combined clinical LR was available for comparison with the PP4 Supporting threshold LR >=2.08. Details ▾Hide ▴
Reasoning

The ENIGMA specification restricts PP4 to a combined clinical likelihood ratio based on clinically calibrated multifactorial data. Its literal pathogenic-direction thresholds are LR >=2.08 for Supporting, LR >=4.3 for Moderate, LR >=18.7 for Strong, and LR >=350 for Very Strong. No exact BRCA2 clinical-history LR entry, combined clinical LR, phenotype-specific likelihood data, or other calibrated PP4 evidence was available for NM_000059.4:c.7141_7147dup. The gene-specific clinical-history table was searched for 7141_7147dup, c.7141_7147dup, 7141, and 7147 with no entry found.

Rule
Use only a combined clinically calibrated multifactorial LR; PP4 Supporting requires LR >=2.08, Moderate >=4.3, Strong >=18.7, or Very Strong >=350.
Evidence considered
  • The ENIGMA specification states that PP4 is used only for combined LR towards pathogenicity based on multifactorial likelihood clinical data, with Supporting LR >=2.08, Moderate LR >=4.3, Strong LR >=18.7, and Very Strong LR >=350.
  • The BRCA2-specific clinical-history LR table was searched for the exact variant forms 7141_7147dup, c.7141_7147dup, 7141, and 7147; no variant-level entry was found.
  • Li et al. and Easton et al. were governing methodology sources for PP4/BP5, but no variant-specific likelihood result for NM_000059.4:c.7141_7147dup was available.
Still missing
  • No exact-variant clinical-history LR or combined multifactorial clinical LR was found.
  • No calibrated variant-specific phenotype, tumour pathology, co-occurrence, family-history, or segregation likelihood components were available.
Sources
cspec ↗vcep_pmid_31853058_brca2_clinical_history_lrPMID:31853058 ↗PMID:17924331 ↗
PP5 Not assessed: no exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification was available to trigger PP5. Details ▾Hide ▴
Reasoning

The ENIGMA specification marks PP5 as do not use, but this assessment applies the requested exact-variant ClinVar expert-panel override. The case contains no ClinVar variation ID, classification, review status, or expert-panel assertion for NM_000059.4:c.7141_7147dup. Ordinary laboratory submissions, aggregate labels, and non-expert assertions therefore cannot trigger PP5, and no qualifying expert-panel Pathogenic or Likely pathogenic classification is available.

Rule
Requested override: apply PP5 only for an exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification; laboratory, aggregate, and non-expert assertions do not qualify.
Evidence considered
  • The ENIGMA specification says PP5 is not to be used; under the requested override, only an exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification would qualify.
  • The case ClinVar record has no variation ID, classification, review status, or submissions for NM_000059.4:c.7141_7147dup.
Still missing
  • No exact-variant ClinVar expert-panel classification or variation identifier was available.
  • The ClinVar evidence record contains no submissions or review status for this variant.
Sources
cspec ↗
BA1 Not assessed: no variant-specific gnomAD FAF, coverage, or quality-filter data are available to compare with the VCEP threshold of >0.001. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 specification applies BA1 when the maximum non-founder gnomAD filter allele frequency, considered separately for exomes and genomes, exceeds 0.001, with read depth at least 20 and no failed quality filter. The case evidence contains no variant-specific gnomAD FAF, read-depth, or quality-filter result for NM_000059.4:c.7141_7147dup, so BA1 cannot be adjudicated.

Rule
BA1: Apply when filter allele frequency is above 0.1% (FAF > 0.001) in gnomAD v2.1 non-cancer exomes and/or gnomAD v3.1 non-cancer genomes in a non-founder population; do not apply if read depth <20 or the variant failed quality control.
Evidence considered
  • The ENIGMA BRCA2 specification defines BA1 as maximum non-founder gnomAD FAF >0.001, evaluated separately for exome and genome data, with read depth >=20 and exclusion of failed quality filters.
  • The case bundle reports gnomAD v2.1 and v4.1 source_data as null and contains no variant-specific population-frequency observation for NM_000059.4:c.7141_7147dup.
Still missing
  • Variant-specific gnomAD v2.1 non-cancer exome and gnomAD v3.1 non-cancer genome FAF, coverage, and quality-filter results are not available in this case.
  • The searched file Specifications_V1.2_2024-11-18.docx.txt contains the BA1 rule but no entry for NM_000059.4:c.7141_7147dup.
  • The searched file Appendices_V1.2_2024-11-18.docx.txt was searched for the population-frequency appendix but yielded no variant-specific entry for NM_000059.4:c.7141_7147dup.
Sources
cspec ↗
BS1 Not assessed: no variant-specific gnomAD FAF is available to compare with the VCEP BS1 thresholds of >0.00002 to >0.0001. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 specification assigns BS1 Strong when non-founder gnomAD v2.1 non-cancer exome or v3.1 non-cancer genome FAF is >0.0001, and BS1 Supporting when FAF is >0.00002 and <=0.0001, with adequate coverage and quality. No variant-specific FAF, coverage, or quality-filter result is available for NM_000059.4:c.7141_7147dup, so BS1 cannot be adjudicated.

Rule
BS1: Strong for FAF >0.0001, or Supporting for FAF >0.00002 and <=0.0001, in gnomAD v2.1 non-cancer exomes and/or gnomAD v3.1 non-cancer genomes in non-founder populations; apply only with adequate coverage and quality.
Evidence considered
  • The ENIGMA BRCA2 specification defines BS1 Strong as FAF >0.0001 and BS1 Supporting as FAF >0.00002 and <=0.0001 in specified non-cancer, non-founder gnomAD populations.
  • The case bundle reports no variant-specific gnomAD population-frequency result for NM_000059.4:c.7141_7147dup.
Still missing
  • Variant-specific gnomAD v2.1 non-cancer exome and gnomAD v3.1 non-cancer genome FAF, coverage, and quality-filter results are not available in this case.
  • The searched file Specifications_V1.2_2024-11-18.docx.txt contains the BS1 thresholds but no entry for NM_000059.4:c.7141_7147dup.
  • The searched file Appendices_V1.2_2024-11-18.docx.txt was searched for the population-frequency appendix but yielded no variant-specific entry for NM_000059.4:c.7141_7147dup.
Sources
cspec ↗
BS2 Not assessed: no healthy-adult genotype/co-occurrence or Fanconi-anemia phenotype data are available to assign the VCEP point score. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 specification applies BS2 using a point system for co-occurring variants in individuals without features of BRCA2-related Fanconi anemia: at least 4 points for BS2 Strong, 2 for Moderate, and 1 for Supporting. The case contains no healthy-adult genotype/co-occurrence or Fanconi-anemia phenotype evidence, so no BS2 strength can be assigned.

Rule
BS2: Apply only using the ENIGMA Table 8 point system for co-occurring variants in individuals without features of BRCA1/2-related Fanconi anemia; >=4 points Strong, 2 points Moderate, and 1 point Supporting.
Evidence considered
  • The ENIGMA BRCA2 specification defines BS2 through Table 8 point scoring for individuals with co-occurring variants and an unlikely Fanconi-anemia phenotype: 4 or more points Strong, 2 Moderate, and 1 Supporting.
  • The case evidence contains no individual-level healthy-adult, co-occurrence, or Fanconi-anemia phenotype data for this duplication.
Still missing
  • No eligible phenotyped individual-level BS2 observations, co-occurring pathogenic or likely pathogenic variants, or Fanconi-anemia phenotype assessments are available.
  • The searched file Specifications_V1.2_2024-11-18.docx.txt contains the BS2 point-system rule but no entry for NM_000059.4:c.7141_7147dup.
  • The searched file Appendices_V1.2_2024-11-18.docx.txt was searched for the BS2-related material but yielded no variant-specific entry for NM_000059.4:c.7141_7147dup.
Sources
cspec ↗
BS3 Not assessed: no variant-specific calibrated benign functional assay result for c.7141_7147dup was found in the governing ENIGMA sources or case evidence. Details ▾Hide ▴
Reasoning

The governing ENIGMA BRCA2 VCEP specification requires BS3 for well-established calibrated functional studies showing no damaging effect on protein function, or on mRNA and protein together; mRNA-only evidence is handled under the alternative BP7 (RNA) framework. The variant NM_000059.4:c.7141_7147dup was searched in Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, Specifications_Table9_V1.2_2024-11-18.xlsx.txt, and HUMU-40-1557-s001.xlsx.txt, with no variant-specific functional-assay entry found. The case-evidence bundle contains no functional assay finding or relevant extracted publication for this variant. Therefore, BS3 cannot be assigned.

Rule
Well-established in vitro or in vivo functional studies showing no damaging effect on protein function; apply BS3 for assays measuring protein effect alone or mRNA and protein combined. Use the calibrated assay recommendations in ENIGMA Specifications Table 9. mRNA-only benign evidence is handled under BP7 (RNA), not BS3.
Evidence considered
  • The ENIGMA BRCA2 VCEP specification states that BS3 requires well-established in vitro or in vivo studies showing no damaging protein effect, or no damaging effect measured through mRNA and protein together, and directs calibrated assay lookups to Table 9.
  • The ENIGMA Table 9 text states that its listed calibrated assay results provide PS3/BS3 code recommendations and that additional published assays require review under the VCEP functional-assay recommendations.
  • Searches of Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, Specifications_Table9_V1.2_2024-11-18.xlsx.txt, and HUMU-40-1557-s001.xlsx.txt found no entry for NM_000059.4:c.7141_7147dup or an equivalent notation.
  • The case-evidence bundle reports no PMIDs and contains no variant-specific functional assay finding for this case.
Still missing
  • No entry for NM_000059.4:c.7141_7147dup or an equivalent notation was found in Specifications_Table9_V1.2_2024-11-18.xlsx.txt.
  • No variant-specific functional evidence was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No variant-specific functional evidence was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No variant-specific functional evidence was found in HUMU-40-1557-s001.xlsx.txt.
  • No case-level functional assay result or relevant paper extraction was present in the functional evidence bundle.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18vcep_specifications_table9_v1_2_2024_11_18vcep_humu_40_1557_s001
BS4 Not assessed: no affected-relative non-segregation data or quantitative likelihood ratio was available to reach the ENIGMA BS4 threshold of LR ≤0.48:1. Details ▾Hide ▴
Reasoning

No affected relatives who tested negative, pedigree, parental testing, phase information, meioses, or quantitative non-segregation likelihood ratio was documented for NM_000059.4:c.7141_7147dup. Under ENIGMA v1.2, BS4 requires quantitatively measured lack of segregation; without those data, no BS4 strength can be assigned.

Rule
Apply weight as per Bayes Score: BS4_Supporting - LR ≤0.48:1; BS4_Moderate - LR ≤0.23:1; BS4 - LR ≤0.05:1; BS4_Very Strong - LR ≤0.00285:1. Lack of segregation must be measured quantitatively.
Evidence considered
  • ENIGMA v1.2 specifies BS4 as quantitatively measured lack of segregation in affected family members, with BS4 Supporting at LR ≤0.48:1, BS4 Moderate at LR ≤0.23:1, BS4 Strong at LR ≤0.05:1, and BS4 Very Strong at LR ≤0.00285:1.
  • The case evidence records no affected relatives who tested negative, pedigree, parental testing, phase, meioses, or non-segregation LR for NM_000059.4:c.7141_7147dup.
  • The searched VCEP variant tables did not provide a usable variant-specific non-segregation result.
Still missing
  • No affected-relative pedigree or tested-family-member data were available for NM_000059.4:c.7141_7147dup.
  • No quantitative non-segregation LR, meiosis count, or phase information was available.
  • No entry for this variant was found when searching Specifications_Table4_V1.2_2024-11-18.xlsx; this table is not applicable to BS4.
  • No entry for this variant was found when searching HUMU-40-1557-s001.xlsx; the file contains no usable segregation result for this variant.
  • SupplementaryTables_V1.2_2024-11-18.xlsx full text was unavailable for the requested lookup, so it could not be independently searched for a variant-specific BS4/PS4 table entry.
Sources
cspec ↗
BP5 Not assessed: no variant-specific clinical LR was available for the BP5 Supporting inequality LR <=0.48. Details ▾Hide ▴
Reasoning

The ENIGMA specification restricts BP5 to a combined clinical likelihood ratio against pathogenicity based on multifactorial clinical data. Its literal benign-direction thresholds are LR <=0.48 for Supporting, LR <=0.23 for Moderate, LR <=0.05 for Strong, and LR <=0.00285 for Very Strong; the explicit Supporting comparison is LR <=0.48. No exact BRCA2 clinical-history LR entry, combined clinical LR, or calibrated benign-direction clinical evidence was available for NM_000059.4:c.7141_7147dup. The gene-specific clinical-history table was searched for 7141_7147dup, c.7141_7147dup, 7141, and 7147 with no entry found.

Rule
Use only a combined clinically calibrated multifactorial LR against pathogenicity; BP5 Supporting requires LR <=0.48, Moderate <=0.23, Strong <=0.05, or Very Strong <=0.00285.
Evidence considered
  • The ENIGMA specification states: BP5 Supporting requires LR <=0.48 to >0.23, Moderate LR <=0.23, Strong LR <=0.05, and Very Strong LR <=0.00285.
  • The decisive BP5 Supporting comparison is therefore LR <=0.48; no variant-specific LR value was available, so no substituted inequality can be evaluated.
  • The BRCA2-specific clinical-history LR table was searched for the exact variant forms 7141_7147dup, c.7141_7147dup, 7141, and 7147; no variant-level entry was found.
  • Li et al. and Easton et al. were governing methodology sources for PP4/BP5, but no variant-specific likelihood result for NM_000059.4:c.7141_7147dup was available.
Still missing
  • No exact-variant clinical-history LR or combined multifactorial clinical LR was found.
  • No calibrated benign-direction phenotype, tumour pathology, co-occurrence, family-history, or segregation likelihood components were available.
Sources
cspec ↗vcep_pmid_31853058_brca2_clinical_history_lrPMID:31853058 ↗PMID:17924331 ↗
BP6 Not assessed: no exact-variant ClinVar expert-panel Benign or Likely benign classification was available to trigger BP6. Details ▾Hide ▴
Reasoning

The ENIGMA specification marks BP6 as do not use, but this assessment applies the requested exact-variant ClinVar expert-panel override. The case contains no ClinVar variation ID, classification, review status, or expert-panel assertion for NM_000059.4:c.7141_7147dup. Ordinary laboratory submissions, aggregate labels, and non-expert assertions therefore cannot trigger BP6, and no qualifying expert-panel Benign or Likely benign classification is available.

Rule
Requested override: apply BP6 only for an exact-variant ClinVar expert-panel Benign or Likely benign classification; laboratory, aggregate, and non-expert assertions do not qualify.
Evidence considered
  • The ENIGMA specification says BP6 is not to be used; under the requested override, only an exact-variant ClinVar expert-panel Benign or Likely benign classification would qualify.
  • The case ClinVar record has no variation ID, classification, review status, or submissions for NM_000059.4:c.7141_7147dup.
Still missing
  • No exact-variant ClinVar expert-panel classification or variation identifier was available.
  • The ClinVar evidence record contains no submissions or review status for this variant.
Sources
cspec ↗
Not applicable · 13· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/ANot applicable: c.7141_7147dup produces p.(Tyr2383SerfsTer11), not a missense substitution or precisely matching splice event eligible for PS1. Details ▾Hide ▴
Reasoning

The variant is NM_000059.4:c.7141_7147dup, predicted to cause p.(Tyr2383SerfsTer11), not a missense substitution or an equivalent splice event. The ENIGMA BRCA2 specification limits PS1 to a same-amino-acid pathogenic missense change or a precisely matching pathogenic splice event; neither applies here. The governing VCEP files contained no entry for this variant notation.

Rule
ENIGMA BRCA2 PS1 applies to predicted missense substitutions sharing a pathogenic amino-acid change, or to variants with the same predicted splicing impact as a known (likely) pathogenic variant.
Evidence considered
  • The case normalization record identifies NM_000059.4:c.7141_7147dup with predicted protein consequence p.(Tyr2383SerfsTer11), a frameshift.
  • ENIGMA PS1 requires a previously pathogenic same-amino-acid missense change or a precisely matching splice event; this frameshift does not meet either condition.
Still missing
  • No entry for NM_000059.4:c.7141_7147dup, c.7141_7147dup, or p.(Tyr2383SerfsTer11) was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No entry for NM_000059.4:c.7141_7147dup, c.7141_7147dup, or p.(Tyr2383SerfsTer11) was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No entry for NM_000059.4:c.7141_7147dup, c.7141_7147dup, or p.(Tyr2383SerfsTer11) was found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt.
Sources
cspec ↗vcep_appendices_v1_2_2024_11_18vcep_specifications_table4_v1_2_2024_11_18
PS2 VCEPNot applicable: ENIGMA explicitly prohibits PS2 because de novo occurrences lack calibrated predictive capacity for BRCA2-related cancers. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1/2 VCEP specification explicitly states that PS2 is not to be used because BRCA1/2-related cancers are relatively common and the predictive capacity of de novo occurrences is not calibrated.

VCEP rule
Do not use. BRCA1/2-related cancers occur relatively commonly. No information to calibrate the predictive capacity of de novo occurrences.
Evidence considered
  • ENIGMA BRCA1/2 ACMG/AMP Specification v1.2, Table 1: PS2 is designated Do not use; the stated reason is that BRCA1/2-related cancers occur relatively commonly and de novo predictive capacity is uncalibrated.
Sources
cspec ↗
PM1 VCEPNot applicable: the frameshift begins at Tyr2383, outside ENIGMA BRCA2 domains aa 10-40 and aa 2481-3186, with no authoritative domain-table entry. Details ▾Hide ▴
Reasoning

The authoritative vcep_materials.json domain_tables key has no gene-specific entry. Under the governing ENIGMA specification, the clinically important BRCA2 domains are the PALB2-binding domain at amino acids 10-40 and the DNA-binding domain at amino acids 2481-3186. The predicted frameshift begins at Tyr2383, outside both listed domains, and PM1 is marked as not applicable in the VCEP framework for this evidence pathway.

VCEP rule
ENIGMA BRCA2 PM1 is not applicable as an independent criterion; the listed clinically important domains are PALB2 binding aa 10-40 and DNA binding aa 2481-3186.
Evidence considered
  • vcep_materials.json has an empty domain_tables object, so no extracted gene-specific domain table supersedes the VCEP specification.
  • ENIGMA defines BRCA2 clinically important domains as PALB2 binding aa 10-40 and DNA binding aa 2481-3186; the frameshift starts at Tyr2383, outside these intervals.
  • The ENIGMA framework marks PM1 as not applicable and treats it as part of the PP3/BP4 bioinformatic analysis rather than an independent code.
Sources
cspec ↗vcep_appendices_v1_2_2024_11_18
PM2 N/ANot applicable: ENIGMA explicitly excludes insertion, deletion, and delins variants from PM2. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 specification limits PM2 to a supporting code for variants absent from the specified non-cancer gnomAD control subsets with regional average read depth at least 25, but explicitly states that PM2 must not be applied to insertion, deletion, or delins variants. NM_000059.4:c.7141_7147dup is a duplication, so PM2 is not applicable regardless of population observations.

Rule
PM2 Supporting: absent from controls in gnomAD v2.1 non-cancer exomes and gnomAD v3.1 non-cancer genomes with regional average read depth >=25; do not apply for insertion, deletion, or delins variants.
Evidence considered
  • The ENIGMA BRCA2 specification states that PM2 is Supporting only when absent from gnomAD v2.1 non-cancer exomes and gnomAD v3.1 non-cancer genomes with regional average read depth >=25.
  • The same specification explicitly states: do not apply PM2 for insertion, deletion, or delins variants; this case variant is a duplication.
Sources
cspec ↗
PM4 VCEPNot applicable: ENIGMA v1.2 explicitly excludes PM4, and this variant is a frameshift null variant rather than an in-frame or stop-loss change. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1/2 specification v1.2 explicitly marks PM4 as not applicable and instructs that protein length changes from in-frame insertions/deletions or stop-loss variants are not used as PM4 in this framework. This variant is instead a frameshift null variant evaluated under PVS1.

VCEP rule
ENIGMA BRCA1/2 v1.2 PM4 rule: Do not use; considered as a component of bioinformatic analysis.
Evidence considered
  • ENIGMA BRCA1/2 specification v1.2 states for PM4: do not use; protein length changes are considered as a component of bioinformatic analysis.
  • The variant consequence is a frameshift with a premature termination codon, not an in-frame insertion/deletion or stop-loss variant.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
PM6 VCEPNot applicable: ENIGMA explicitly prohibits PM6 because de novo occurrences lack calibrated predictive capacity for BRCA2-related cancers. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1/2 VCEP specification explicitly states that PM6 is not to be used because BRCA1/2-related cancers are relatively common and the predictive capacity of de novo occurrences is not calibrated.

VCEP rule
Do not use. BRCA1/2-related cancers occur relatively commonly. No information to calibrate the predictive capacity of de novo occurrences.
Evidence considered
  • ENIGMA BRCA1/2 ACMG/AMP Specification v1.2, Table 1: PM6 is designated Do not use; the stated reason is that BRCA1/2-related cancers occur relatively commonly and de novo predictive capacity is uncalibrated.
Sources
cspec ↗
PP2 VCEPNot applicable: ENIGMA explicitly marks PP2 as not applicable, and this variant is a frameshift duplication rather than a missense change. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 VCEP framework explicitly marks PP2 as not applicable. In addition, this variant is a frameshift duplication rather than a missense variant, so the generic PP2 missense mechanism criterion is not relevant.

VCEP rule
ENIGMA BRCA2 PP2 is not applicable.
Evidence considered
  • The ENIGMA BRCA2 framework lists PP2 as Not Applicable.
  • The normalized consequence is a frameshift duplication, not a missense variant.
Sources
cspec ↗
PP3 N/ANot applicable: c.7141_7147dup creates p.(Tyr2383SerfsTer11), a frameshift outside PP3's missense, in-frame, silent, and intronic/splice-region scope. Details ▾Hide ▴
Reasoning

PP3 is not applicable because NM_000059.4:c.7141_7147dup is an exonic duplication producing the frameshift protein consequence p.(Tyr2383SerfsTer11), not a missense, in-frame, silent, or intronic/splice-region variant within this criterion's scope. The ENIGMA BRCA2 specification limits PP3 to missense or in-frame variants with protein-impact predictions, or predicted splicing for silent, missense/in-frame, and eligible intronic variants; therefore SpliceAI, BayesDel, REVEL, and other computational predictors were not evaluated. The governing Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, and PMID_22505045_Houdayer_2012_HumMutat.pdf.txt contained no variant-level entry for 7141, 7147, c.7141_7147dup, or p.(Tyr2383SerfsTer11).

Rule
ENIGMA BRCA2 v1.2 PP3 scope: missense/in-frame protein-impact prediction or predicted splicing for silent, missense/in-frame, and eligible intronic variants; do not apply to frameshift variants.
Evidence considered
  • The normalized case evidence identifies NM_000059.4:c.7141_7147dup and the predicted consequence p.(Tyr2383SerfsTer11), an exonic frameshift.
  • The ENIGMA BRCA2 specification states that PP3 applies to missense/in-frame protein-impact predictions or predicted splicing for silent, missense/in-frame, and eligible intronic variants; frameshift variants are outside this computational criterion's scope.
  • The three declared full-text files were searched for 7141, 7147, c.7141_7147dup, p.(Tyr2383SerfsTer11), duplication, and frameshift; no variant-level entry was found.
Still missing
  • No variant-level entry for NM_000059.4:c.7141_7147dup, 7141, 7147, or p.(Tyr2383SerfsTer11) was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No variant-level entry for NM_000059.4:c.7141_7147dup, 7141, 7147, or p.(Tyr2383SerfsTer11) was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No variant-level entry for NM_000059.4:c.7141_7147dup, 7141, 7147, or p.(Tyr2383SerfsTer11) was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18vcep_pmid_22505045_houdayer_2012_hummutat
BP1 N/ANot applicable: BP1 requires a silent, missense, or in-frame variant, whereas c.7141_7147dup is a frameshift duplication producing p.(Tyr2383SerfsTer11). Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 BP1 rule is restricted to silent, missense, or in-frame insertion/deletion/delins variants outside a clinically important domain with no predicted splicing impact. NM_000059.4:c.7141_7147dup is a frameshift duplication producing p.(Tyr2383SerfsTer11), not an eligible variant class; therefore BP1 cannot be applied.

Rule
ENIGMA BRCA2 BP1_Strong applies to silent, missense, or in-frame insertion/deletion/delins variants outside aa 10-40 or aa 2481-3186 with SpliceAI <=0.1.
Evidence considered
  • The case normalization record identifies c.7141_7147dup as a frameshift duplication with p.(Tyr2383SerfsTer11).
  • ENIGMA BP1 eligibility is limited to silent, missense, or in-frame insertion/deletion/delins variants outside the specified functional domains and without predicted splicing impact.
Sources
cspec ↗
BP2 VCEPNot applicable: the ENIGMA BRCA2 specification explicitly excludes BP2 and limits related co-observation assessment to BS2. Details ▾Hide ▴
Reasoning

The governing ENIGMA BRCA2 VCEP specification explicitly marks BP2 as not applicable and states that it is applied only in the context of BS2. Therefore, BP2 is not assigned for NM_000059.4:c.7141_7147dup, regardless of whether any cis or trans co-observation might otherwise be reported.

VCEP rule
BP2: Do not use; applied only in the context of BS2.
Evidence considered
  • The ENIGMA BRCA2 VCEP specification lists BP2 as Do not use and states that it is applied only in the context of BS2.
  • The governing specification file was searched for c.7141_7147dup, 7141_7147dup, and p.(Tyr2383SerfsTer11); no variant-specific BP2 entry was found, but the explicit criterion-level exclusion governs.
Sources
vcep_specifications_v1_2_2024_11_18
BP3 VCEPNot applicable: ENIGMA v1.2 excludes BP3, which applies only to in-frame repeat-region insertions/deletions without known function. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1/2 specification v1.2 explicitly marks BP3 as not applicable and reserves it for in-frame insertions/deletions in repetitive regions without known function. This variant is a pathogenic-appearing frameshift duplication with a premature termination codon, not an in-frame repeat-region alteration.

VCEP rule
ENIGMA BRCA1/2 v1.2 BP3 rule: Do not use; in-frame deletions/insertions in a repetitive region without a known function are captured by bioinformatic prediction and domain analysis.
Evidence considered
  • ENIGMA BRCA1/2 specification v1.2 states for BP3: do not use; it is captured by bioinformatic tool prediction and domain analysis.
  • The variant is a 7-bp frameshift duplication producing p.(Tyr2383SerfsTer11), not an in-frame insertion or deletion in a repetitive region.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
BP4 N/ANot applicable: c.7141_7147dup creates p.(Tyr2383SerfsTer11), a frameshift outside BP4's missense, in-frame, silent, and intronic/splice-region scope. Details ▾Hide ▴
Reasoning

BP4 is not applicable because NM_000059.4:c.7141_7147dup is an exonic duplication producing the frameshift protein consequence p.(Tyr2383SerfsTer11), not a missense, in-frame, silent, or intronic/splice-region variant within this criterion's scope. The ENIGMA BRCA2 specification limits BP4 to no predicted protein or splicing impact for specified missense/in-frame, silent, or eligible intronic variants; therefore SpliceAI, BayesDel, REVEL, and other computational predictors were not evaluated. The governing Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, and PMID_22505045_Houdayer_2012_HumMutat.pdf.txt contained no variant-level entry for 7141, 7147, c.7141_7147dup, or p.(Tyr2383SerfsTer11).

Rule
ENIGMA BRCA2 v1.2 BP4 scope: no predicted protein or splicing impact for specified missense/in-frame, silent, and eligible intronic variants; do not apply to frameshift variants.
Evidence considered
  • The normalized case evidence identifies NM_000059.4:c.7141_7147dup and the predicted consequence p.(Tyr2383SerfsTer11), an exonic frameshift.
  • The ENIGMA BRCA2 specification states that BP4 applies to no predicted protein or splicing impact for specified missense/in-frame, silent, or eligible intronic variants; frameshift variants are outside this computational criterion's scope.
  • The three declared full-text files were searched for 7141, 7147, c.7141_7147dup, p.(Tyr2383SerfsTer11), duplication, and frameshift; no variant-level entry was found.
Still missing
  • No variant-level entry for NM_000059.4:c.7141_7147dup, 7141, 7147, or p.(Tyr2383SerfsTer11) was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No variant-level entry for NM_000059.4:c.7141_7147dup, 7141, 7147, or p.(Tyr2383SerfsTer11) was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No variant-level entry for NM_000059.4:c.7141_7147dup, 7141, 7147, or p.(Tyr2383SerfsTer11) was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18vcep_pmid_22505045_houdayer_2012_hummutat
BP7 N/ANot applicable: c.7141_7147dup creates p.(Tyr2383SerfsTer11), a frameshift rather than a synonymous variant required for BP7. Details ▾Hide ▴
Reasoning

BP7 is not applicable because NM_000059.4:c.7141_7147dup is an exonic duplication producing the frameshift protein consequence p.(Tyr2383SerfsTer11), not a synonymous variant. BP7 is restricted to silent/synonymous variants, including the ENIGMA BRCA2 RNA-specific and splicing-impact pathways; no predictor evaluation is required for this out-of-scope frameshift. The governing Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, and PMID_22505045_Houdayer_2012_HumMutat.pdf.txt contained no variant-level entry for 7141, 7147, c.7141_7147dup, or p.(Tyr2383SerfsTer11).

Rule
ENIGMA BRCA2 v1.2 BP7 scope: silent/synonymous variants with appropriate benign RNA or splicing evidence; do not apply to frameshift variants.
Evidence considered
  • The normalized case evidence identifies NM_000059.4:c.7141_7147dup and the predicted consequence p.(Tyr2383SerfsTer11), an exonic frameshift rather than a synonymous substitution.
  • The ENIGMA BRCA2 specification restricts BP7 to silent/synonymous variants and related RNA evidence; frameshift variants are outside BP7's scope.
  • The three declared full-text files were searched for 7141, 7147, c.7141_7147dup, p.(Tyr2383SerfsTer11), duplication, and frameshift; no variant-level entry was found.
Still missing
  • No variant-level entry for NM_000059.4:c.7141_7147dup, 7141, 7147, or p.(Tyr2383SerfsTer11) was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No variant-level entry for NM_000059.4:c.7141_7147dup, 7141, 7147, or p.(Tyr2383SerfsTer11) was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No variant-level entry for NM_000059.4:c.7141_7147dup, 7141, 7147, or p.(Tyr2383SerfsTer11) was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18vcep_pmid_22505045_houdayer_2012_hummutat

Identifiers

Gene
BRCA2
Coding (HGVS c.)
NM_000059.4:7141_7147dup
Location and type
unknown
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 0 / 0 alleles AF 0 · 0 homozygotes · FAF 0

By genetic ancestry

gnomAD-Canada

AF 0 · 0 / 0 alleles · 0 hom

Statements

No population statements were recorded.

Open the gnomAD-Canada detail page →

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 N/ANot applicable: c.7141_7147dup creates p.(Tyr2383SerfsTer11), a frameshift outside PP3's missense, in-frame, silent, and intronic/splice-region scope. Details ▾Hide ▴
Reasoning

PP3 is not applicable because NM_000059.4:c.7141_7147dup is an exonic duplication producing the frameshift protein consequence p.(Tyr2383SerfsTer11), not a missense, in-frame, silent, or intronic/splice-region variant within this criterion's scope. The ENIGMA BRCA2 specification limits PP3 to missense or in-frame variants with protein-impact predictions, or predicted splicing for silent, missense/in-frame, and eligible intronic variants; therefore SpliceAI, BayesDel, REVEL, and other computational predictors were not evaluated. The governing Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, and PMID_22505045_Houdayer_2012_HumMutat.pdf.txt contained no variant-level entry for 7141, 7147, c.7141_7147dup, or p.(Tyr2383SerfsTer11).

Rule
ENIGMA BRCA2 v1.2 PP3 scope: missense/in-frame protein-impact prediction or predicted splicing for silent, missense/in-frame, and eligible intronic variants; do not apply to frameshift variants.
Evidence considered
  • The normalized case evidence identifies NM_000059.4:c.7141_7147dup and the predicted consequence p.(Tyr2383SerfsTer11), an exonic frameshift.
  • The ENIGMA BRCA2 specification states that PP3 applies to missense/in-frame protein-impact predictions or predicted splicing for silent, missense/in-frame, and eligible intronic variants; frameshift variants are outside this computational criterion's scope.
  • The three declared full-text files were searched for 7141, 7147, c.7141_7147dup, p.(Tyr2383SerfsTer11), duplication, and frameshift; no variant-level entry was found.
Still missing
  • No variant-level entry for NM_000059.4:c.7141_7147dup, 7141, 7147, or p.(Tyr2383SerfsTer11) was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No variant-level entry for NM_000059.4:c.7141_7147dup, 7141, 7147, or p.(Tyr2383SerfsTer11) was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No variant-level entry for NM_000059.4:c.7141_7147dup, 7141, 7147, or p.(Tyr2383SerfsTer11) was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18vcep_pmid_22505045_houdayer_2012_hummutat
BP4 N/ANot applicable: c.7141_7147dup creates p.(Tyr2383SerfsTer11), a frameshift outside BP4's missense, in-frame, silent, and intronic/splice-region scope. Details ▾Hide ▴
Reasoning

BP4 is not applicable because NM_000059.4:c.7141_7147dup is an exonic duplication producing the frameshift protein consequence p.(Tyr2383SerfsTer11), not a missense, in-frame, silent, or intronic/splice-region variant within this criterion's scope. The ENIGMA BRCA2 specification limits BP4 to no predicted protein or splicing impact for specified missense/in-frame, silent, or eligible intronic variants; therefore SpliceAI, BayesDel, REVEL, and other computational predictors were not evaluated. The governing Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, and PMID_22505045_Houdayer_2012_HumMutat.pdf.txt contained no variant-level entry for 7141, 7147, c.7141_7147dup, or p.(Tyr2383SerfsTer11).

Rule
ENIGMA BRCA2 v1.2 BP4 scope: no predicted protein or splicing impact for specified missense/in-frame, silent, and eligible intronic variants; do not apply to frameshift variants.
Evidence considered
  • The normalized case evidence identifies NM_000059.4:c.7141_7147dup and the predicted consequence p.(Tyr2383SerfsTer11), an exonic frameshift.
  • The ENIGMA BRCA2 specification states that BP4 applies to no predicted protein or splicing impact for specified missense/in-frame, silent, or eligible intronic variants; frameshift variants are outside this computational criterion's scope.
  • The three declared full-text files were searched for 7141, 7147, c.7141_7147dup, p.(Tyr2383SerfsTer11), duplication, and frameshift; no variant-level entry was found.
Still missing
  • No variant-level entry for NM_000059.4:c.7141_7147dup, 7141, 7147, or p.(Tyr2383SerfsTer11) was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No variant-level entry for NM_000059.4:c.7141_7147dup, 7141, 7147, or p.(Tyr2383SerfsTer11) was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No variant-level entry for NM_000059.4:c.7141_7147dup, 7141, 7147, or p.(Tyr2383SerfsTer11) was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18vcep_pmid_22505045_houdayer_2012_hummutat
BP7 N/ANot applicable: c.7141_7147dup creates p.(Tyr2383SerfsTer11), a frameshift rather than a synonymous variant required for BP7. Details ▾Hide ▴
Reasoning

BP7 is not applicable because NM_000059.4:c.7141_7147dup is an exonic duplication producing the frameshift protein consequence p.(Tyr2383SerfsTer11), not a synonymous variant. BP7 is restricted to silent/synonymous variants, including the ENIGMA BRCA2 RNA-specific and splicing-impact pathways; no predictor evaluation is required for this out-of-scope frameshift. The governing Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, and PMID_22505045_Houdayer_2012_HumMutat.pdf.txt contained no variant-level entry for 7141, 7147, c.7141_7147dup, or p.(Tyr2383SerfsTer11).

Rule
ENIGMA BRCA2 v1.2 BP7 scope: silent/synonymous variants with appropriate benign RNA or splicing evidence; do not apply to frameshift variants.
Evidence considered
  • The normalized case evidence identifies NM_000059.4:c.7141_7147dup and the predicted consequence p.(Tyr2383SerfsTer11), an exonic frameshift rather than a synonymous substitution.
  • The ENIGMA BRCA2 specification restricts BP7 to silent/synonymous variants and related RNA evidence; frameshift variants are outside BP7's scope.
  • The three declared full-text files were searched for 7141, 7147, c.7141_7147dup, p.(Tyr2383SerfsTer11), duplication, and frameshift; no variant-level entry was found.
Still missing
  • No variant-level entry for NM_000059.4:c.7141_7147dup, 7141, 7147, or p.(Tyr2383SerfsTer11) was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No variant-level entry for NM_000059.4:c.7141_7147dup, 7141, 7147, or p.(Tyr2383SerfsTer11) was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No variant-level entry for NM_000059.4:c.7141_7147dup, 7141, 7147, or p.(Tyr2383SerfsTer11) was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18vcep_pmid_22505045_houdayer_2012_hummutat

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

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

COSMIC Captured COSMIC 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.

Somatic

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