0%
BRCA2c.2988C>TUncertain significance
Print report
Variant interpretation report

BRCA2 c.2988C>T, p.Leu996=

NM_000059.4:c.2988C>T NP_000050.3:p.(Leu996=) Synonymous · exon 11 View identifiers
Classification
Uncertain significance

Variant description:

The BRCA2 NM_000059.4:c.2988C>T (NP_000050.3:p.(Leu996=)) synonymous variant has not previously been reported in somatic cancers (COSMIC). Based on available guidelines, this variant is considered to be a Variant of Uncertain Significance (VUS).

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

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About BRCA2

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

NCBI Gene ↗ OncoKB ↗
LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
01The reasoning

How it was classified

The recorded framework is ClinGen BRCA2 VCEP v1.2. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 0 Benign evidence criteria: 0
Pathogenic criteria applied · 0

No pathogenic criterion marked as applied in the recorded assessment.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

VUS: no pathogenic or benign criteria are applied under the ENIGMA BRCA2 VCEP Table 3 rules; all criteria are not applicable or not assessed.

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
1 / 1,613,732 alleles

gnomAD v4.1: 1 / 1,613,732 alleles. Recorded AF 6.19682e-07. Recorded homozygote count 0.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

No listed criterion applied
gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗
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
ClinVar submissions
3 reported laboratory submissions

3 Likely benign. ClinVar API review status: criteria provided, multiple submitters, no conflicts.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported

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

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under ClinGen BRCA2 VCEP v1.2, with the data and sources behind each one.

28 criteria with recorded statuses: 0 met · 0 not met · 16 not assessed · 12 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

PVS1, PM4, and BP3 are all not applicable under the ENIGMA BRCA2 VCEP rules because NM_000059.4:c.2988C>T is a synonymous exon 11 substitution with no protein-length change and is not an in-frame indel, stop-loss, null, or canonical splice-site variant.

PP3 is not_assessed because the VCEP-required SpliceAI >=0.2 value is unavailable.

BP4 is not_applicable because the synonymous variant is outside the VCEP's defined BRCA2 functional domains and is not intronic.

BP7 is not_assessed because its outside-domain RNA path requires a qualifying mRNA-only assay that is unavailable; its ordinary silent-variant path is limited to variants inside a functional domain with BP4 met.

Not assessed · 16 · no assessment recorded

PS1 VCEPNot assessed: no SpliceAI score or VCEP-file entry establishes the same pathogenic splicing impact required for this synonymous variant. Details ▾Hide ▴
Reasoning

The variant is synonymous (p.(Leu996=)), so the VCEP's PS1 missense route does not apply. The alternative VCEP route requires an exonic or intronic variant with the same predicted splicing impact as a previously classified (likely) pathogenic variant, with weight varied by relative position and confidence in the reference classification. SpliceAI returned no score, and searches of Specifications_V1.2_2024-11-18.docx, SupplementaryTables_V1.2_2024-11-18.xlsx, Appendices_V1.2_2024-11-18.docx, and Specifications_Table4_V1.2_2024-11-18.xlsx found no entry for c.2988C>T, p.Leu996=, or p.L996= establishing a qualifying pathogenic comparator or pre-assigned PS1 code. PS1 therefore cannot be assessed from the available VCEP evidence.

VCEP rule
Apply **PS1**, for predicted **missense** substitutions, where a previously classified **pathogenic** variant is considered to act via protein change (no confirmed or predicted effect on mRNA splicing (SpliceAI≤0.1)). ... Apply **PS1**, for exonic and intronic variants with same predicted impact on **splicing,** as a previously classified **pathogenic** variant. Vary weight depending on relative positions, and confidence in classification of the reference variant.
Evidence considered
  • Case normalization: NM_000059.4:c.2988C>T, NP_000050.3:p.(Leu996=) / p.(L996=), synonymous variant.
  • The VCEP PS1 rule distinguishes missense protein-change evidence from exonic/intronic variants with the same predicted splicing impact as a previously classified (likely) pathogenic variant.
  • SpliceAI was unavailable (no score; timeout), so the required predicted splicing comparison cannot be made.
  • Direct searches of all four governing files for c.2988C>T, p.Leu996=, and p.L996= returned no matching entries.
Still missing
  • No entry for c.2988C>T, p.Leu996=, or p.L996= was found in Specifications_V1.2_2024-11-18.docx.
  • No entry for c.2988C>T, p.Leu996=, or p.L996= was found in SupplementaryTables_V1.2_2024-11-18.xlsx.
  • No entry for c.2988C>T, p.Leu996=, or p.L996= was found in Appendices_V1.2_2024-11-18.docx.
  • No entry for c.2988C>T, p.Leu996=, or p.L996= was found in Specifications_Table4_V1.2_2024-11-18.xlsx.
  • SpliceAI returned no score for this variant.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗
PS3 VCEPNot assessed: the ENIGMA functional-assay table has no row for c.2988C>T, p.Leu996=, or p.L996= and no variant-specific damaging assay result is available. Details ▾Hide ▴
Reasoning

PS3 is applicable in this VCEP framework to well-established functional studies showing a damaging effect when the assay measures protein alone or mRNA and protein together. The governing Table 9 file contains calibrated assay recommendations, but searches for c.2988C>T, p.Leu996=, and p.L996= found no row for this variant. No variant-specific functional assay evidence for NM_000059.4:c.2988C>T is present in the case evidence, so the criterion cannot be assessed without substituting evidence or calibration outside the ENIGMA BRCA2 VCEP materials.

VCEP rule
Well-established in vitro or in vivo functional studies supportive of a damaging effect. Apply PS3 for assays measuring effect via protein only OR mRNA and protein combined. See Specifications Table 9 for code recommendations from calibrated published assays. Also see Figure1C and Appendix E for details.
Evidence considered
  • Specifications_Table9_V1.2_2024-11-18.xlsx, sheet Table9_BRCA12VCEP_specs: the table states that it summarizes BRCA1/2 functional assay results reviewed for PS3 and BS3 and that additional published assay results require review under Figure 1C; no row matched c.2988C>T, p.Leu996=, or p.L996=.
  • Case normalization identifies NM_000059.4:c.2988C>T as synonymous, NP_000050.3:p.(Leu996=)/p.(L996=); the case bundle contains no variant-specific functional assay result for this variant.
Still missing
  • No matching entry for c.2988C>T, p.Leu996=, or p.L996= in Specifications_Table9_V1.2_2024-11-18.xlsx.txt.
  • No matching entry for c.2988C>T, p.Leu996=, or p.L996= in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No matching entry for c.2988C>T, p.Leu996=, or p.L996= in Specifications_V1.2_2024-11-18.docx.txt.
  • No matching entry for c.2988C>T, p.Leu996=, or p.L996= in Appendices_V1.2_2024-11-18.docx.txt.
  • No matching entry for c.2988C>T, p.Leu996=, or p.L996= in HUMU-40-1557-s001.xlsx.txt.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_specifications_table9_v1_2_2024_11_18 ↗
PS4 VCEPNot assessed: no target-variant case-control counts, odds ratio, confidence interval, or p-value were available to test the ENIGMA PS4 thresholds. Details ▾Hide ▴
Reasoning

The ENIGMA rule requires a case-control study with p-value <=0.05, OR >=4, and a lower confidence interval excluding 2.0; it also requires ethnicity- and country-matched cases and controls. The governing SupplementaryTables_V1.2_2024-11-18.xlsx ST7 Reference Set contains no entry for c.2988C>T, p.Leu996=, or p.L996=; the only nearby BRCA2 entry found was c.2987T>G p.(Leu996Arg), which is a different variant. HUMU-40-1557-s001 likewise contains no row for the target variant. The literature_pass.json packet has no ai_classified_papers, and the reviewed candidate papers do not report this variant or variant-specific case-control counts. Therefore the required OR, confidence interval, and p-value cannot be evaluated; this is not evidence that case-control evidence is absent.

VCEP rule
The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls. ... Case-control studies; p-value ≤0.05 and OR ≥4 (lower confidence interval excludes 2.0). ... Case dataset should be ethnicity and country-matched to control dataset.
Evidence considered
  • Specifications_V1.2_2024-11-18.docx, PS4 rule: prevalence in affected individuals must be significantly increased versus controls; case-control studies require p-value <=0.05 and OR >=4, with the lower confidence interval excluding 2.0.
  • Specifications_V1.2_2024-11-18.docx, PS4 stipulation: the case dataset should be ethnicity- and country-matched to the control dataset.
  • SupplementaryTables_V1.2_2024-11-18.xlsx, ST7 Reference Set: no target-variant row; c.2987T>G p.(Leu996Arg) is a different variant and cannot be substituted.
  • HUMU-40-1557-s001.xlsx, SuppT1 All Data: no target-variant row found.
  • The reviewed candidate papers PMID:12692171, PMID:17508274, PMID:20065170, and PMID:26324357 provide general hereditary-cancer guidance and no target-variant case-control data.
Still missing
  • No c.2988C>T, p.Leu996=, or p.L996= entry was found in SupplementaryTables_V1.2_2024-11-18.xlsx.
  • No c.2988C>T, p.Leu996=, or p.L996= row was found in HUMU-40-1557-s001.xlsx.
  • The reviewed literature packet contains no variant-specific case-control counts or statistics for this variant.
Sources
cspec ↗vcep_supplementarytables_v1_2_2024_11_18 ↗vcep_humu_40_1557_s001 ↗PMID:31131967 ↗PMID:12692171 ↗PMID:17508274 ↗PMID:20065170 ↗PMID:26324357 ↗
PM2 VCEPNot assessed: the variant is absent from both required non-cancer gnomAD datasets, but the VCEP-required regional average read depth of at least 25 is unavailable. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 v1.2 PM2_Supporting rule requires absence from controls in an outbred population in gnomAD v2.1 non-cancer exomes and gnomAD v3.1 non-cancer genomes, with regional average read depth at least 25; the specification also states that a single observation in a gnomAD outbred population is not informative. The variant is reported absent from both required non-cancer datasets, but no regional read-depth value is available. The criterion therefore cannot be applied under the VCEP rule.

VCEP rule
Absent/rare from controls in an ethnically-matched cohort population sample. ... Absent from gnomAD (exome and genome). ... Preferred datasets to use: gnomAD v2.1 non-cancer, exomes gnomAD v3.1 non-cancer, genomes ... Observation of a variant only once in a gnomAD outbred population is not informative (no code applied). Do not apply for insertion, deletion or delins variants. Do not apply if read depth <25 at region around the variant. Exclude data if variant failed quality control filter.
Evidence considered
  • ENIGMA CSPEC BRCA2 v1.2 PM2_Supporting rule: absence from gnomAD v2.1 non-cancer exomes and gnomAD v3.1 non-cancer genomes, with regional average read depth ≥25; one observation in a gnomAD outbred population is not informative.
  • GNOMAD_V2_1_NON_CANCER: absent from gnomAD v2.1 non-cancer; no regional read-depth value was provided.
  • GNOMAD_V3_1_NON_CANCER: absent from gnomAD v3.1 non-cancer; no regional read-depth value was provided.
Still missing
  • Required regional average read depth is unavailable; PM2 requires average read depth ≥25.
  • No matching entry for c.2988C>T, p.Leu996=, or p.L996= was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No matching entry for c.2988C>T, p.Leu996=, or p.L996= was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No matching entry for c.2988C>T, p.Leu996=, or p.L996= was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No matching entry for c.2988C>T, p.Leu996=, or p.L996= was found in HUMU-40-1557-s001.xlsx.txt.
Sources
cspec ↗gnomad_v2 ↗
PM3 VCEPNot assessed: no Fanconi Anemia phenotype, co-occurring BRCA2 pathogenic variant, phase, or PM3 point assignment is documented for this variant. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 PM3 rule requires a patient with a phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia and co-occurrent variants in the same gene, with PM3 strength assigned from Table 6 points. The case evidence bundle contains no affected-proband Fanconi Anemia phenotype, chromosome-breakage result, second BRCA2 pathogenic/likely pathogenic variant, phase, or co-occurrence observation for NM_000059.4:c.2988C>T (p.Leu996=). Searching Specifications_V1.2_2024-11-18.docx.txt for c.2988C>T, p.Leu996=, and p.L996= found no variant-specific entry; this is a gap in the governing file, not evidence that the allelic evidence is absent.

VCEP rule
Apply for patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia (FA), and co-occurrent variants in the same gene. Phenotype is considered consistent with BRCA1- or BRCA2-related FA if: (i) Increased chromosome breakage (DEB, MMC, or spontaneous) and at least one clinical feature indicative of BRCA1/2-related FA, categorized under: physical features, pathology and laboratory findings, cancer diagnosis ≤5yr. (ii) Result unknown for chromosome breakage, and at least two clinical features indicative of BRCA1/2-related FA under at least two of the three categories: physical features, pathology and laboratory findings, cancer diagnosis ≤5yr. See Appendix H ... Co-occurrent P or LP variant should be assigned classification using VCEP specifications. ... Variant under assessment must be sufficiently rare (not meeting a benign population evidence code). ... See Table 6 for approach to assign points per proband, and final PM3 code assignment based on the sum of PM3-related points.
Evidence considered
  • ClinGen ENIGMA BRCA2 PM3 rule: applies only to a patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia and co-occurrent variants in the same gene; Table 6 assigns points by phase and phenotype.
  • The consolidated case-evidence bundle contains no affected-proband Fanconi Anemia phenotype, chromosome-breakage result, co-occurring BRCA2 pathogenic/likely pathogenic variant, or phase observation for NM_000059.4:c.2988C>T (p.Leu996=).
  • Specifications_V1.2_2024-11-18.docx.txt was searched for c.2988C>T, p.Leu996=, and p.L996=; no variant-specific entry was found.
Still missing
  • No variant-specific entry was found in /Users/gs_agent/LYFESCI_HERMES_v11/vcep_db/BRCA2/fulltext/Specifications_V1.2_2024-11-18.docx.txt for c.2988C>T, p.Leu996=, or p.L996=.
  • Affected-proband Fanconi Anemia phenotype and chromosome-breakage data are not documented.
  • A co-occurring BRCA2 pathogenic/likely pathogenic variant and its phase relative to c.2988C>T are not documented.
Sources
cspec ↗
PP1 VCEPNot assessed: no quantitative co-segregation likelihood ratio or family-level segregation data is available for c.2988C>T. Details ▾Hide ▴
Reasoning

The VCEP requires quantitative co-segregation evidence and assigns PP1 strength from a pathogenicity likelihood ratio. The case evidence contains no affected-family segregation analysis, proband count, parental testing, meioses, or quantitative co-segregation LR for NM_000059.4:c.2988C>T. The governing VCEP files were searched for c.2988C>T, p.Leu996=, and p.L996=; no variant-specific entry was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt, Specifications_V1.2_2024-11-18.docx.txt, or HUMU-40-1557-s001.xlsx.txt.

VCEP rule
Co-segregation with disease in multiple affected family members ... 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 ... Stipulation: to apply code as Pathogenic Very Strong, VUS should have bioinformatically predicted (or experimentally proven) effect on protein or mRNA splicing. If co-segregation score is from a single family, or several families from an isolated population, assess the possibility of a different causative pathogenic variant.
Evidence considered
  • ENIGMA BRCA2 Specifications v1.2, Table 1: PP1 requires co-segregation with disease in multiple affected family members measured by a quantitative co-segregation method, with strength determined by LR.
  • Case evidence provides no quantitative co-segregation LR or family-level segregation observations for NM_000059.4:c.2988C>T.
  • Parsons et al. 2019 HUMU-40-1557-s001 was searched for c.2988C>T, p.Leu996=, and p.L996=; its converted text contains a different BRCA2 row, c.2987T>G p.(Leu996Arg), not this variant.
Still missing
  • No variant-specific entry for c.2988C>T, p.Leu996=, or p.L996= was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No variant-specific entry for c.2988C>T, p.Leu996=, or p.L996= was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No variant-specific entry for c.2988C>T, p.Leu996=, or p.L996= was found in HUMU-40-1557-s001.xlsx.txt.
  • No affected-family segregation analysis, parental testing, meioses, or quantitative co-segregation LR is present in the case evidence bundle.
Sources
vcep_specifications_v1_2_2024_11_18 ↗
PP3 VCEPNot assessed: SpliceAI returned no score, so the ENIGMA >=0.2 predicted-splicing threshold cannot be evaluated. Details ▾Hide ▴
Reasoning

The ENIGMA rule makes PP3 applicable to predicted splicing in silent variants irrespective of functional-domain location, using SpliceAI >=0.2. This synonymous exon 11 variant has no SpliceAI score because the service timed out, and the searched ENIGMA SupplementaryTables, Specifications, Appendices, and Houdayer full-text files contain no entry for c.2988C>T, p.Leu996=, or p.L996=; therefore the governing threshold cannot be evaluated.

VCEP rule
Apply PP3 for predicted splicing (SpliceAI ≥0.2) for silent, missense/in-frame (irrespective of location in clinically important functional domain) and for intronic variants outside of the donor and acceptor ±1,2 positions.
Evidence considered
  • Case normalization identifies NM_000059.4:c.2988C>T as synonymous, NP_000050.3:p.(Leu996=), exon 11.
  • The case evidence reports spliceai_available=false, max_delta_score=null, and a timeout; Pangolin values are not used because the governing rule names SpliceAI.
  • ENIGMA PP3 scope: predicted splicing (SpliceAI >=0.2) applies to silent variants irrespective of functional-domain location.
  • The governing VCEP files were searched for c.2988C>T, p.Leu996=, and p.L996=; no variant-specific pre-assigned PP3 code or splice result was found.
Still missing
  • No SpliceAI score is available; the case evidence records a timeout and explicitly treats this as missing data.
  • No entry for c.2988C>T, p.Leu996=, or p.L996= was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No entry for c.2988C>T, p.Leu996=, or p.L996= was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No entry for c.2988C>T, p.Leu996=, or p.L996= was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No entry for c.2988C>T, p.Leu996=, or p.L996= was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗PMID:22505045 ↗
PP4 VCEPNot assessed: no target-specific multifactorial clinical likelihood ratio was available for comparison with the ENIGMA PP4 threshold of LR >=2.08:1. Details ▾Hide ▴
Reasoning

ENIGMA PP4 is restricted to combined clinically calibrated multifactorial likelihood data. Supporting PP4 requires LR >=2.08:1, with higher strengths requiring LR >=4.3:1, >=18.7:1, or >=350:1. No exact c.2988C>T row was found in the governing Li et al. BRCA2 clinical-history LR table, and no exact target row was found in the Parsons multifactorial table or ENIGMA ST7. The available evidence therefore supplies no target-specific combined clinical LR for comparison; the criterion is not assessed rather than inferred from ClinVar's likely-benign classification or from unrelated variants.

VCEP rule
Breast cancer is very common and has a high degree of genetic heterogeneity (caused by pathogenic variants in numerous genes). Use ONLY to capture combined LR towards pathogenicity, based on multifactorial likelihood clinical data. ... PP4 - LR ≥2.08:1 ... PP4_Moderate – LR≥4.3:1 ... PP4_Strong – LR≥18.7:1 ... PP4_Very Strong – LR≥350:1
Evidence considered
  • Specifications_V1.2_2024-11-18.docx, PP4 rule: use only combined LR towards pathogenicity based on multifactorial likelihood clinical data; PP4 Supporting requires LR >=2.08:1, Moderate >=4.3:1, Strong >=18.7:1, and Very Strong >=350:1.
  • PMID_31853058_BRCA2_clinical_history_LR.xlsx, Sheet1: no exact BRCA2 c.2988C>T row was found; the table is therefore not a source of a target-specific LR.
  • HUMU-40-1557-s001.xlsx, SuppT1 All Data and SupplementaryTables_V1.2_2024-11-18.xlsx, ST7 Reference Set: no exact target row was found.
Still missing
  • No exact BRCA2 c.2988C>T row was found in PMID_31853058_BRCA2_clinical_history_LR.xlsx.
  • No exact target row was found in HUMU-40-1557-s001.xlsx or SupplementaryTables_V1.2_2024-11-18.xlsx.
Sources
cspec ↗vcep_pmid_31853058_brca2_clinical_history_lr ↗PMID:31853058 ↗vcep_humu_40_1557_s001 ↗PMID:31131967 ↗vcep_supplementarytables_v1_2_2024_11_18 ↗PMID:17924331 ↗
BA1 VCEPNot assessed: gnomAD v4.1 AF is 6.1968e-07, far below the 0.001 BA1 threshold, but required VCEP read-depth data are unavailable. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 v1.2 rule requires FAF above 0.001 in gnomAD v2.1 non-cancer exomes and/or gnomAD v3.1 non-cancer genomes, using a non-founder population, and prohibits application when read depth is below 20 or when the variant fails quality control. The case evidence reports the variant absent from GNOMAD_V2_1_NON_CANCER and GNOMAD_V3_1_NON_CANCER, while all-comers gnomAD v4.1 reports AF 6.196815828154861e-07, maximum observed subpopulation AF 8.47532324882871e-07, and zero homozygotes. However, the required regional read depth and applicable filter allele frequency quality data are not available, so BA1 cannot be applied or excluded under the VCEP rule.

VCEP rule
Above 0.001 (0.1%) ... Apply based on maximum filter allele frequency observed in a gnomAD non-founder population, considering exome and genome data separately. Do not apply if read depth <20. Do not apply to well-established pathogenic founder variants. Exclude data if variant failed quality control filter.
Evidence considered
  • ENIGMA CSPEC BRCA2 v1.2 BA1 rule: FAF must be above 0.001 in gnomAD v2.1 non-cancer exomes and/or gnomAD v3.1 non-cancer genomes, with maximum FAF considered separately by exome and genome.
  • GNOMAD_V2_1_NON_CANCER: absent from gnomAD v2.1 non-cancer; no source_data or read-depth value was provided.
  • GNOMAD_V3_1_NON_CANCER: absent from gnomAD v3.1 non-cancer; no source_data or read-depth value was provided.
  • gnomAD v4.1 all-comers: AF 6.196815828154861e-07, 1/1613732 alleles, maximum observed subpopulation AF 8.47532324882871e-07 in European (non-Finnish), homozygotes 0.
Still missing
  • Required regional read depth and applicable FAF quality data are unavailable.
  • No matching entry for c.2988C>T, p.Leu996=, or p.L996= was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No matching entry for c.2988C>T, p.Leu996=, or p.L996= was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No matching entry for c.2988C>T, p.Leu996=, or p.L996= was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No matching entry for c.2988C>T, p.Leu996=, or p.L996= was found in HUMU-40-1557-s001.xlsx.txt.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗
BS1 VCEPNot assessed: gnomAD v4.1 maximum AF is 8.4753e-07, below the 0.00002 BS1-supporting threshold, but required VCEP read-depth data are unavailable. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 v1.2 rule requires maximum FAF above 0.0001 for BS1 or above 0.00002 and at most 0.0001 for BS1_Supporting in gnomAD v2.1 non-cancer exomes and/or gnomAD v3.1 non-cancer genomes, with separate exome/genome assessment and a read-depth threshold of 20. The variant is absent from both required non-cancer datasets; all-comers gnomAD v4.1 shows AF 6.196815828154861e-07 and maximum observed subpopulation AF 8.47532324882871e-07, below both BS1 ranges. Required regional read depth and FAF quality data are unavailable, so the VCEP application gate cannot be evaluated.

VCEP rule
BS1 - above 0.0001 (0.01%) BS1_Supporting - >0.00002 (0.002%) to ≤ 0.0001 (0.01%). ... Apply based on maximum filter allele frequency in a gnomAD non-founder population, considering exome and genome data separately. Do not apply if read depth <20. Do not apply to well-established pathogenic founder variants. Exclude data if variant failed quality control filter.
Evidence considered
  • ENIGMA CSPEC BRCA2 v1.2 BS1 rule: BS1 requires FAF above 0.0001; BS1_Supporting requires FAF above 0.00002 and at most 0.0001, in the specified non-cancer datasets.
  • GNOMAD_V2_1_NON_CANCER: absent from gnomAD v2.1 non-cancer; no source_data or read-depth value was provided.
  • GNOMAD_V3_1_NON_CANCER: absent from gnomAD v3.1 non-cancer; no source_data or read-depth value was provided.
  • gnomAD v4.1 all-comers: AF 6.196815828154861e-07 and maximum observed subpopulation AF 8.47532324882871e-07, both below 0.00002; homozygotes 0.
Still missing
  • Required regional read depth and applicable FAF quality data are unavailable.
  • No matching entry for c.2988C>T, p.Leu996=, or p.L996= was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No matching entry for c.2988C>T, p.Leu996=, or p.L996= was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No matching entry for c.2988C>T, p.Leu996=, or p.L996= was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No matching entry for c.2988C>T, p.Leu996=, or p.L996= was found in HUMU-40-1557-s001.xlsx.txt.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗
BS2 VCEPNot assessed: gnomAD reports zero homozygotes, but no qualifying healthy-adult observation or VCEP BS2 point-system data are available. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 v1.2 BS2 rule requires observations in healthy adults, with the applicable variable weight determined from the VCEP's BS2 point system and absence of Fanconi Anemia features. The available population data report zero homozygotes but do not identify a healthy adult observation, individual phenotype, age/follow-up, trans phase, co-occurring pathogenic variant, or BS2 points. Therefore BS2 cannot be assessed from the available evidence.

VCEP rule
Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age ... Applied in absence of features of recessive disease, namely Fanconi Anemia phenotype. ... See Table 8 for approach to assign points per proband, and final BS2 code assignment based on the sum of BS2-related points.
Evidence considered
  • ENIGMA CSPEC BRCA2 v1.2 BS2 rule: BS2 is applied in the absence of Fanconi Anemia features and requires the VCEP Table 8 point approach; no qualifying individual-level observation is available.
  • gnomAD v4.1 all-comers: 1 alternate allele, zero homozygotes; this is population aggregate data and does not establish a qualifying healthy-adult BS2 observation.
Still missing
  • No qualifying healthy-adult individual observation, Fanconi Anemia assessment, phase, age/follow-up, or BS2 point assignment is available.
  • No matching entry for c.2988C>T, p.Leu996=, or p.L996= was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No matching entry for c.2988C>T, p.Leu996=, or p.L996= was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No matching entry for c.2988C>T, p.Leu996=, or p.L996= was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No matching entry for c.2988C>T, p.Leu996=, or p.L996= was found in HUMU-40-1557-s001.xlsx.txt.
Sources
cspec ↗gnomad_v4 ↗
BS3 VCEPNot assessed: the ENIGMA functional-assay table has no row for c.2988C>T, p.Leu996=, or p.L996= and no variant-specific benign assay result is available. Details ▾Hide ▴
Reasoning

BS3 is applicable in this VCEP framework to well-established functional studies showing no damaging effect when the assay measures protein alone or mRNA and protein together. The governing Table 9 file contains calibrated assay recommendations, but searches for c.2988C>T, p.Leu996=, and p.L996= found no row for this variant. No variant-specific functional assay evidence for NM_000059.4:c.2988C>T is present in the case evidence, so the criterion cannot be assessed without substituting evidence or calibration outside the ENIGMA BRCA2 VCEP materials.

VCEP rule
Well-established in vitro or in vivo functional studies shows no damaging effect on protein function. Assay measures effect via protein only OR mRNA and protein combined. See Specifications Table 9 for code recommendations from calibrated published assays. Also see Figure1C and Appendix E for details.
Evidence considered
  • Specifications_Table9_V1.2_2024-11-18.xlsx, sheet Table9_BRCA12VCEP_specs: the table states that it summarizes BRCA1/2 functional assay results reviewed for PS3 and BS3 and that additional published assay results require review under Figure 1C; no row matched c.2988C>T, p.Leu996=, or p.L996=.
  • Case normalization identifies NM_000059.4:c.2988C>T as synonymous, NP_000050.3:p.(Leu996=)/p.(L996=); the case bundle contains no variant-specific functional assay result for this variant.
Still missing
  • No matching entry for c.2988C>T, p.Leu996=, or p.L996= in Specifications_Table9_V1.2_2024-11-18.xlsx.txt.
  • No matching entry for c.2988C>T, p.Leu996=, or p.L996= in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No matching entry for c.2988C>T, p.Leu996=, or p.L996= in Specifications_V1.2_2024-11-18.docx.txt.
  • No matching entry for c.2988C>T, p.Leu996=, or p.L996= in Appendices_V1.2_2024-11-18.docx.txt.
  • No matching entry for c.2988C>T, p.Leu996=, or p.L996= in HUMU-40-1557-s001.xlsx.txt.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_specifications_table9_v1_2_2024_11_18 ↗
BS4 VCEPNot assessed: no quantitative lack-of-segregation likelihood ratio or affected-family non-segregation data is available for c.2988C>T. Details ▾Hide ▴
Reasoning

The VCEP requires quantitative lack-of-segregation evidence and assigns BS4 strength from a benign likelihood ratio. The case evidence contains no affected-family non-segregation analysis, parental testing, meioses, or quantitative BS4 LR for NM_000059.4:c.2988C>T. The governing VCEP files were searched for c.2988C>T, p.Leu996=, and p.L996=; no variant-specific entry was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt, Specifications_V1.2_2024-11-18.docx.txt, or HUMU-40-1557-s001.xlsx.txt.

VCEP rule
Lack of segregation in affected members of a family. ... Apply weight as per Bayes Score: ... BS4_Supporting - LR ≤0.48 to >0.23:1 ... BS4_Moderate - LR ≤0.23:1 ... BS4 - LR ≤0.05:1 ... BS4_Very strong – LR ≤0.00285:1 ... Stipulation: To apply code as Benign Very Strong, assess the possibility of bi-linearity to explain negative co-segregation.
Evidence considered
  • ENIGMA BRCA2 Specifications v1.2, Table 1: BS4 requires lack of segregation in affected family members measured by a quantitative co-segregation method, with strength determined by LR.
  • Case evidence provides no quantitative lack-of-segregation LR or affected-family non-segregation observations for NM_000059.4:c.2988C>T.
  • Parsons et al. 2019 HUMU-40-1557-s001 was searched for c.2988C>T, p.Leu996=, and p.L996=; its converted text contains a different BRCA2 row, c.2987T>G p.(Leu996Arg), not this variant.
Still missing
  • No variant-specific entry for c.2988C>T, p.Leu996=, or p.L996= was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No variant-specific entry for c.2988C>T, p.Leu996=, or p.L996= was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No variant-specific entry for c.2988C>T, p.Leu996=, or p.L996= was found in HUMU-40-1557-s001.xlsx.txt.
  • No affected-family non-segregation analysis, parental testing, meioses, or quantitative lack-of-segregation LR is present in the case evidence bundle.
Sources
vcep_specifications_v1_2_2024_11_18 ↗
BP1 VCEPNot assessed: residue 996 is outside listed domains, but the required SpliceAI ≤0.1 no-splicing condition is unavailable. Details ▾Hide ▴
Reasoning

The VCEP BP1 rule requires a silent substitution outside a clinically important functional domain and no predicted splicing, defined by SpliceAI ≤0.1. Residue 996 is outside the VCEP-listed BRCA2 domains aa 10-40 and aa 2481-3186, but SpliceAI returned no score for this variant. Because the required no-splicing condition cannot be evaluated, BP1 cannot be assigned.

VCEP rule
**Apply BP1_Strong** for silent substitution, missense or in-frame insertion, deletion or delins variants outside a (potentially) clinically important functional domain AND no splicing predicted (SpliceAI ≤0.1). ... (potentially) clinically important functional domains are defined as: BRCA2 PALB2 binding domain aa 10-40; BRCA2 DNA binding aa 2481-3186.
Evidence considered
  • Variant normalization identifies a silent substitution at residue 996.
  • The VCEP lists clinically important BRCA2 domains as aa 10-40 and aa 2481-3186; residue 996 is outside both.
  • The case evidence reports SpliceAI unavailable with no score; missing data is not evidence of no splice impact.
  • Direct searches of all four governing files for c.2988C>T, p.Leu996=, and p.L996= returned no matching entries.
Still missing
  • No entry for c.2988C>T, p.Leu996=, or p.L996= was found in Specifications_V1.2_2024-11-18.docx.
  • No entry for c.2988C>T, p.Leu996=, or p.L996= was found in SupplementaryTables_V1.2_2024-11-18.xlsx.
  • No entry for c.2988C>T, p.Leu996=, or p.L996= was found in Appendices_V1.2_2024-11-18.docx.
  • No entry for c.2988C>T, p.Leu996=, or p.L996= was found in Specifications_Table4_V1.2_2024-11-18.xlsx.
  • SpliceAI returned no score for this variant, so SpliceAI ≤0.1 cannot be established.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗
BP5 VCEPNot assessed: no target-specific multifactorial LR was available to test the BP5 Supporting inequality LR <=0.48:1. Details ▾Hide ▴
Reasoning

ENIGMA BP5 may be used only for a combined LR against pathogenicity from multifactorial clinical data. The criterion's supporting threshold is LR <=0.48:1, with Moderate <=0.23:1, Strong <=0.05:1, and Very Strong <=0.00285:1. No exact target-variant row was found in the Li et al. BRCA2 clinical-history LR table, Parsons multifactorial table, or ST7 Reference Set, so no target-specific LR can be substituted or compared. The explicit inequality cannot be formed from available target-specific evidence; BP5 is not assessed.

VCEP rule
Use ONLY to capture combined LR against pathogenicity, based on multifactorial likelihood clinical data. ... BP5_VeryStrong – LR ≤0.00285:1 ... BP5_Strong - LR ≤0.05:1 ... BP5_Moderate - LR ≤0.23:1 ... BP5 - LR ≤0.48 to >0.23:1
Evidence considered
  • Specifications_V1.2_2024-11-18.docx, BP5 rule: use only combined LR against pathogenicity based on multifactorial likelihood clinical data; BP5 Supporting requires LR <=0.48:1, Moderate <=0.23:1, Strong <=0.05:1, and Very Strong <=0.00285:1.
  • The required Supporting comparison is LR <=0.48:1; no target-specific LR is available, so no numeric inequality can be evaluated.
  • PMID_31853058_BRCA2_clinical_history_LR.xlsx, HUMU-40-1557-s001.xlsx, and SupplementaryTables_V1.2_2024-11-18.xlsx: no exact target row found.
Still missing
  • No exact BRCA2 c.2988C>T row was found in PMID_31853058_BRCA2_clinical_history_LR.xlsx.
  • No exact target row was found in HUMU-40-1557-s001.xlsx or SupplementaryTables_V1.2_2024-11-18.xlsx.
Sources
cspec ↗vcep_pmid_31853058_brca2_clinical_history_lr ↗PMID:31853058 ↗vcep_humu_40_1557_s001 ↗PMID:31131967 ↗vcep_supplementarytables_v1_2_2024_11_18 ↗PMID:17924331 ↗
BP7 VCEPNot assessed: outside-domain BP7 requires a qualifying mRNA-only assay, but no such assay result is available. Details ▾Hide ▴
Reasoning

The ordinary ENIGMA BP7 path requires a silent variant inside a clinically important functional domain and BP4 met, which does not fit this exon 11 variant outside the named domains. However, the VCEP separately repurposes BP7_Strong (RNA) for silent variants outside a clinically important domain when a well-established mRNA-only functional study shows no damaging effect. No such mRNA assay is present in the available evidence, and the SpliceAI result is missing, so BP7 cannot be assessed on either path.

VCEP rule
Well-established in vitro or in vivo functional studies shows no damaging effect on protein function as measured by effect on mRNA transcript profile – mRNA assay only. ... Apply as BP7_Strong (RNA) for intronic, silent, and missense/in-frame variants located outside a (potentially) clinically important functional domain.
Evidence considered
  • Case normalization identifies the variant as synonymous at p.Leu996= in exon 11, outside the ENIGMA BRCA2 domains aa 10-40 and aa 2481-3186.
  • ENIGMA ordinary BP7 applies to silent variants inside a clinically important domain if BP4 is met; ENIGMA BP7_Strong (RNA) applies to silent variants outside a domain only with a well-established mRNA-only functional study showing no damaging effect.
  • No qualifying mRNA-only assay result was found in the case evidence or the searched governing files.
  • The governing VCEP files were searched for c.2988C>T, p.Leu996=, and p.L996=; no variant-specific pre-assigned BP7 code was found.
Still missing
  • No qualifying well-established mRNA-only functional assay result showing no damaging effect is available for this variant.
  • SpliceAI returned no score, so the ordinary BP7 path's BP4 prerequisite cannot be evaluated; the missing score is not evidence of no splice impact.
  • No entry for c.2988C>T, p.Leu996=, or p.L996= was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No entry for c.2988C>T, p.Leu996=, or p.L996= was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No entry for c.2988C>T, p.Leu996=, or p.L996= was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No entry for c.2988C>T, p.Leu996=, or p.L996= was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗PMID:22505045 ↗
Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANot applicable: c.2988C>T is synonymous, whereas ENIGMA PVS1 applies to null or canonical splice-site variants in its decision tree. Details ▾Hide ▴
Reasoning

NM_000059.4:c.2988C>T is a synonymous exon 11 variant, annotated as NP_000050.3:p.(Leu996=). The ENIGMA PVS1 rule is for null variants and its specified decision-tree variant classes are initiation, nonsense/frameshift, deletion, duplication, and canonical donor/acceptor +/-1,2 splice-site variants. This variant is none of those classes and is not a canonical splice-site variant; therefore PVS1 is not applicable. The variant-specific case assessment confirms synonymous consequence and exon 11. No matching entry for this variant was found in Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, Specifications_Table4_V1.2_2024-11-18.xlsx.txt, or PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.

VCEP rule
Null variant in a gene where loss of function is a known mechanism of disease. ... See Table 4, provided as a separate searchable excel file, for a comprehensive summary of codes applicable for all variants considered against the BRCA1 and BRCA2 PVS1 decision trees (initiation, nonsense/frameshift, deletion, duplication, splice site (donor/acceptor ±1,2)) – organized by exon.
Evidence considered
  • Variant assessment: NM_000059.4:c.2988C>T; NP_000050.3:p.(Leu996=); synonymous consequence; exon 11; not a canonical donor/acceptor splice-site variant.
  • ENIGMA Specifications Table 1 and Appendix D govern PVS1 through null-variant classes and the PVS1 decision tree; Table 4 is the exon-level lookup for those classes.
Still missing
  • No matching c.2988C>T, p.Leu996=, or p.L996= entry found in Specifications_V1.2_2024-11-18.docx.txt.
  • No matching c.2988C>T, p.Leu996=, or p.L996= entry found in Appendices_V1.2_2024-11-18.docx.txt.
  • No matching c.2988C>T, p.Leu996=, or p.L996= entry found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt.
  • No matching c.2988C>T, p.Leu996=, or p.L996= entry found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗pvs1_variant_assessmentvcep_specifications_v1_2_2024_11_18 ↗vcep_specifications_table4_v1_2_2024_11_18 ↗
PS2 VCEPNot applicable: the VCEP explicitly prohibits PS2 because de novo occurrences are not calibrated for BRCA1/2-related cancers. Details ▾Hide ▴
Reasoning

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

VCEP rule
De novo (paternity confirmed) in a patient with the disease and no family history. ... Do not use BRCA1/2-related cancers occur relatively commonly. No information to calibrate the predictive capacity of de novo occurrences.
Evidence considered
  • ENIGMA BRCA2 Specifications v1.2, Table 1: PS2 is marked Do not use because no calibration exists for de novo occurrences in relatively common BRCA1/2-related cancers.
Sources
vcep_specifications_v1_2_2024_11_18 ↗
PM1 VCEPNot applicable: the BRCA2 VCEP explicitly marks PM1 Not Applicable, and residue 996 is outside its listed functional domains. Details ▾Hide ▴
Reasoning

The BRCA2 VCEP CSPEC entry explicitly marks PM1 as Not Applicable. The case's vcep_materials domain_tables is empty, and the VCEP's listed functional domains for the related benign missense rule are BRCA2 residues 10-40 and 2481-3186; residue 996 is outside both, with no VCEP-approved PM1 route applicable to this synonymous variant.

VCEP rule
Not Applicable
Evidence considered
  • The BRCA2 CSPEC criteria entry explicitly sets PM1 applicability to Not Applicable.
  • The VCEP domain definition lists BRCA2 PALB2 binding domain aa 10-40 and BRCA2 DNA binding aa 2481-3186; the variant is p.(Leu996=), outside both ranges.
  • No variant-specific entry was found in the four governing VCEP full-text files.
Still missing
  • No entry for c.2988C>T, p.Leu996=, or p.L996= was found in Specifications_V1.2_2024-11-18.docx.
  • No entry for c.2988C>T, p.Leu996=, or p.L996= was found in SupplementaryTables_V1.2_2024-11-18.xlsx.
  • No entry for c.2988C>T, p.Leu996=, or p.L996= was found in Appendices_V1.2_2024-11-18.docx.
  • No entry for c.2988C>T, p.Leu996=, or p.L996= was found in Specifications_Table4_V1.2_2024-11-18.xlsx.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗
PM4 VCEPNot applicable: PM4 is restricted to in-frame length changes or stop-loss variants, while c.2988C>T preserves the Leu996 protein residue. Details ▾Hide ▴
Reasoning

The governing ENIGMA specification defines PM4 for protein-length changes caused by in-frame deletions/insertions in a non-repeat region or stop-loss variants, and explicitly marks PM4 as not used. This variant is synonymous and produces no protein-length change; PM4 is therefore not applicable. No matching entry for this variant was found in Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, Specifications_Table4_V1.2_2024-11-18.xlsx.txt, or PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.

VCEP rule
Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants. ... Do not use ... Considered as component of bioinformatic analysis (PP3/BP4).
Evidence considered
  • Variant assessment: NP_000050.3:p.(Leu996=), a synonymous change with no protein-length alteration.
  • ENIGMA Specifications Table 1 states that PM4 concerns in-frame insertion/deletion protein-length changes or stop-loss variants and is not used.
Still missing
  • No matching c.2988C>T, p.Leu996=, or p.L996= entry found in Specifications_V1.2_2024-11-18.docx.txt.
  • No matching c.2988C>T, p.Leu996=, or p.L996= entry found in Appendices_V1.2_2024-11-18.docx.txt.
  • No matching c.2988C>T, p.Leu996=, or p.L996= entry found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt.
  • No matching c.2988C>T, p.Leu996=, or p.L996= entry found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗pvs1_variant_assessmentvcep_specifications_v1_2_2024_11_18 ↗
PM5 N/ANot applicable: PM5 is limited by this VCEP to PTC variants with a different proven pathogenic PTC in the same exon, not synonymous variants. Details ▾Hide ▴
Reasoning

The BRCA2 VCEP repurposes PM5 for a protein termination codon variant in an exon with a different proven pathogenic PTC variant, as additional weight for a PVS1 annotation. NM_000059.4:c.2988C>T is synonymous (p.(Leu996=)), not a PTC or truncating variant, so the governing PM5 rule does not apply.

VCEP rule
Protein termination codon (PTC) variant in an exon where a different proven pathogenic PTC variant has been seen before. Use to justify additional weight for PTC variants annotated as PVS1. See Specifications Table 4 for PM5_PTC code strengths applicable per exon. See Appendix D for additional details.
Evidence considered
  • Variant consequence is synonymous, p.(Leu996=), not a protein termination codon or other PVS1 truncating variant.
  • The VCEP PM5 rule states that PM5 is for a PTC variant in an exon where a different proven pathogenic PTC variant has been seen before and is additional weight for PVS1.
  • The VCEP Table 4 PM5 applicability table is relevant only to the PTC route; no variant-specific entry was found in the four governing VCEP full-text files.
Still missing
  • No entry for c.2988C>T, p.Leu996=, or p.L996= was found in Specifications_V1.2_2024-11-18.docx.
  • No entry for c.2988C>T, p.Leu996=, or p.L996= was found in SupplementaryTables_V1.2_2024-11-18.xlsx.
  • No entry for c.2988C>T, p.Leu996=, or p.L996= was found in Appendices_V1.2_2024-11-18.docx.
  • No entry for c.2988C>T, p.Leu996=, or p.L996= was found in Specifications_Table4_V1.2_2024-11-18.xlsx.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_specifications_table4_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗
PM6 VCEPNot applicable: the VCEP explicitly prohibits PM6 because de novo occurrences are not calibrated for BRCA1/2-related cancers. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 VCEP explicitly states that PM6 is not to be used because BRCA1/2-related cancers occur relatively commonly and there is no information to calibrate the predictive capacity of de novo occurrences without confirmed paternity and maternity.

VCEP rule
Confirmed de novo without confirmation of paternity and maternity. ... Do not use BRCA1/2-related cancers occur relatively commonly. No information to calibrate the predictive capacity of de novo occurrences.
Evidence considered
  • ENIGMA BRCA2 Specifications v1.2, Table 1: PM6 is marked Do not use because no calibration exists for de novo occurrences in relatively common BRCA1/2-related cancers.
Sources
vcep_specifications_v1_2_2024_11_18 ↗
PP2 VCEPNot applicable: the BRCA2 VCEP explicitly marks PP2 Not Applicable, so no missense-mechanism evidence is assigned. Details ▾Hide ▴
Reasoning

The BRCA2 VCEP CSPEC entry explicitly marks PP2 as Not Applicable. Therefore no gene-level missense-mechanism inference may be assigned under this VCEP for this synonymous variant.

VCEP rule
Not Applicable
Evidence considered
  • The BRCA2 CSPEC criteria entry explicitly sets PP2 applicability to Not Applicable.
  • The variant is synonymous rather than missense.
  • No variant-specific entry was found in the four governing VCEP full-text files.
Still missing
  • No entry for c.2988C>T, p.Leu996=, or p.L996= was found in Specifications_V1.2_2024-11-18.docx.
  • No entry for c.2988C>T, p.Leu996=, or p.L996= was found in SupplementaryTables_V1.2_2024-11-18.xlsx.
  • No entry for c.2988C>T, p.Leu996=, or p.L996= was found in Appendices_V1.2_2024-11-18.docx.
  • No entry for c.2988C>T, p.Leu996=, or p.L996= was found in Specifications_Table4_V1.2_2024-11-18.xlsx.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗
PP5 VCEPNot applicable: the ENIGMA BRCA2 specification explicitly states that PP5 should not be used. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 specification explicitly says not to use PP5. The available ClinVar record is a three-laboratory likely-benign record, not a reputable pathogenic report, and cannot override the VCEP's explicit prohibition.

VCEP rule
Reputable source recently reports variant as pathogenic but the evidence is not available to the laboratory to perform an independent evaluation. ... Do not use
Evidence considered
  • Specifications_V1.2_2024-11-18.docx, PP5: reputable source recently reports variant as pathogenic but evidence is unavailable for independent evaluation; the VCEP instruction is Do not use.
  • ClinVar variation 1159930: three clinical laboratories report Likely benign, with no expert-panel submission; this is not pathogenic PP5 evidence.
Sources
cspec ↗clinvar ↗PMID:12692171 ↗PMID:17508274 ↗PMID:20065170 ↗PMID:26324357 ↗
BP2 VCEPNot applicable: the ENIGMA BRCA2 specification says BP2 is not for use and permits it only in the context of BS2. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 specification explicitly says BP2 is not for use and limits it to the context of BS2. Therefore BP2 is not applicable under this VCEP, regardless of whether phase or co-observation data might otherwise be available.

VCEP rule
Do not use Applied only in the context of BS2.
Evidence considered
  • The CSPEC entry for BP2 states: "Applied only in the context of BS2."
  • Specifications_V1.2_2024-11-18.docx.txt was searched for c.2988C>T, p.Leu996=, and p.L996=; no variant-specific entry was found, while the governing criterion rule itself is explicit.
Sources
cspec ↗
BP3 VCEPNot applicable: BP3 is restricted to in-frame indels in nonfunctional repeats, whereas c.2988C>T is a synonymous single-nucleotide substitution. Details ▾Hide ▴
Reasoning

The governing ENIGMA specification limits BP3 to in-frame deletions/insertions in a repetitive region without a known function and explicitly states that BP3 is not used. This variant is a synonymous single-nucleotide substitution, not an in-frame deletion or insertion; BP3 is therefore not applicable. No matching entry for this variant was found in Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, Specifications_Table4_V1.2_2024-11-18.xlsx.txt, or PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.

VCEP rule
In-frame deletions/insertions in a repetitive region without a known function ... Do not use ... Captured by bioinformatic tool prediction, and domain analysis. See Appendix J.
Evidence considered
  • Variant assessment: NM_000059.4:c.2988C>T is a synonymous single-nucleotide substitution producing p.(Leu996=), not an in-frame deletion or insertion.
  • ENIGMA Specifications Table 1 defines BP3 as in-frame deletions/insertions in a repetitive region without known function and marks it not to be used.
Still missing
  • No matching c.2988C>T, p.Leu996=, or p.L996= entry found in Specifications_V1.2_2024-11-18.docx.txt.
  • No matching c.2988C>T, p.Leu996=, or p.L996= entry found in Appendices_V1.2_2024-11-18.docx.txt.
  • No matching c.2988C>T, p.Leu996=, or p.L996= entry found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt.
  • No matching c.2988C>T, p.Leu996=, or p.L996= entry found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗pvs1_variant_assessmentvcep_specifications_v1_2_2024_11_18 ↗
BP4 N/ANot applicable: p.Leu996 lies outside ENIGMA's aa 10-40 and aa 2481-3186 domains, so silent-variant BP4 does not apply. Details ▾Hide ▴
Reasoning

The ENIGMA BP4 scope includes silent variants only when they are inside a defined clinically important functional domain, or intronic variants outside canonical donor/acceptor positions. This synonymous exon 11 variant encodes p.Leu996=, outside the BRCA2 PALB2-binding domain (aa 10-40) and DNA-binding domain (aa 2481-3186), and is not intronic; BP4 is therefore not_applicable before evaluating the missing SpliceAI result.

VCEP rule
Silent variant inside a (potentially) clinically important functional domain, if no predicted impact via splicing (SpliceAI ≤0.1). ... Intronic variants outside of the donor and acceptor ±1,2 positions AND no predicted impact via splicing (SpliceAI ≤0.1). ... As justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA2 PALB2 binding domain aa 10-40; BRCA2 DNA binding aa 2481-3186.
Evidence considered
  • Case normalization identifies the variant as synonymous at p.Leu996= in exon 11.
  • ENIGMA defines BRCA2 clinically important functional domains as the PALB2 binding domain aa 10-40 and DNA binding aa 2481-3186.
  • The variant's amino-acid position 996 is outside both named BRCA2 domains; the intronic BP4 path is inapplicable because this is an exonic synonymous variant.
  • The governing VCEP files were searched for c.2988C>T, p.Leu996=, and p.L996=; no variant-specific pre-assigned BP4 code was found.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗
BP6 VCEPNot applicable: the ENIGMA BRCA2 specification explicitly states that BP6 should not be used. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 specification explicitly states that BP6 is not to be used. The ClinVar record is likely benign but does not change the VCEP applicability rule.

VCEP rule
Reputable source recently reports variant as benign but the evidence is not available to the laboratory to perform an independent evaluation ... Do not use
Evidence considered
  • Specifications_V1.2_2024-11-18.docx, BP6: reputable source recently reports variant as benign but the evidence is not available for independent evaluation; the VCEP instruction is Do not use.
  • ClinVar variation 1159930 reports Likely benign from three clinical laboratories, but this cannot make a VCEP-prohibited criterion applicable.
Sources
cspec ↗clinvar ↗

Identifiers

Gene
BRCA2
Transcript
NM_000059.4
Coding (HGVS c.)
NM_000059.4:c.2988C>T
Protein (HGVS p.)
NP_000050.3:p.(Leu996=)
GRCh38
chr13:32337343 C>T
GRCh37
chr13:32911480 C>T
Location and type
Exon 11 · synonymous
ClinVar
1159930

Gene diagram

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

BRCA2NM_000059.4
Fetching transcript structure from UCSC…
gnomAD v4.1 1 / 1,613,732 alleles AF 6.2e-07 · 0 homozygotes
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 6.2e-07 · 1 / 1,613,732 alleles · 0 hom
European (non-Finnish)1 / 1,179,896 8.5e-07
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 6.19682e-07; MAF= 0.00006%, 1/1613732 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47532e-07; MAF= 0.00008%, 1/1179896 alleles, homozygotes = 0).

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

SpliceAI and Pangolin

Pangolin splice lossmagnitude shown
-0.001
Pangolin splice gain
0.001

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 VCEPNot assessed: SpliceAI returned no score, so the ENIGMA >=0.2 predicted-splicing threshold cannot be evaluated. Details ▾Hide ▴
Reasoning

The ENIGMA rule makes PP3 applicable to predicted splicing in silent variants irrespective of functional-domain location, using SpliceAI >=0.2. This synonymous exon 11 variant has no SpliceAI score because the service timed out, and the searched ENIGMA SupplementaryTables, Specifications, Appendices, and Houdayer full-text files contain no entry for c.2988C>T, p.Leu996=, or p.L996=; therefore the governing threshold cannot be evaluated.

VCEP rule
Apply PP3 for predicted splicing (SpliceAI ≥0.2) for silent, missense/in-frame (irrespective of location in clinically important functional domain) and for intronic variants outside of the donor and acceptor ±1,2 positions.
Evidence considered
  • Case normalization identifies NM_000059.4:c.2988C>T as synonymous, NP_000050.3:p.(Leu996=), exon 11.
  • The case evidence reports spliceai_available=false, max_delta_score=null, and a timeout; Pangolin values are not used because the governing rule names SpliceAI.
  • ENIGMA PP3 scope: predicted splicing (SpliceAI >=0.2) applies to silent variants irrespective of functional-domain location.
  • The governing VCEP files were searched for c.2988C>T, p.Leu996=, and p.L996=; no variant-specific pre-assigned PP3 code or splice result was found.
Still missing
  • No SpliceAI score is available; the case evidence records a timeout and explicitly treats this as missing data.
  • No entry for c.2988C>T, p.Leu996=, or p.L996= was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No entry for c.2988C>T, p.Leu996=, or p.L996= was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No entry for c.2988C>T, p.Leu996=, or p.L996= was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No entry for c.2988C>T, p.Leu996=, or p.L996= was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗PMID:22505045 ↗
BP7 VCEPNot assessed: outside-domain BP7 requires a qualifying mRNA-only assay, but no such assay result is available. Details ▾Hide ▴
Reasoning

The ordinary ENIGMA BP7 path requires a silent variant inside a clinically important functional domain and BP4 met, which does not fit this exon 11 variant outside the named domains. However, the VCEP separately repurposes BP7_Strong (RNA) for silent variants outside a clinically important domain when a well-established mRNA-only functional study shows no damaging effect. No such mRNA assay is present in the available evidence, and the SpliceAI result is missing, so BP7 cannot be assessed on either path.

VCEP rule
Well-established in vitro or in vivo functional studies shows no damaging effect on protein function as measured by effect on mRNA transcript profile – mRNA assay only. ... Apply as BP7_Strong (RNA) for intronic, silent, and missense/in-frame variants located outside a (potentially) clinically important functional domain.
Evidence considered
  • Case normalization identifies the variant as synonymous at p.Leu996= in exon 11, outside the ENIGMA BRCA2 domains aa 10-40 and aa 2481-3186.
  • ENIGMA ordinary BP7 applies to silent variants inside a clinically important domain if BP4 is met; ENIGMA BP7_Strong (RNA) applies to silent variants outside a domain only with a well-established mRNA-only functional study showing no damaging effect.
  • No qualifying mRNA-only assay result was found in the case evidence or the searched governing files.
  • The governing VCEP files were searched for c.2988C>T, p.Leu996=, and p.L996=; no variant-specific pre-assigned BP7 code was found.
Still missing
  • No qualifying well-established mRNA-only functional assay result showing no damaging effect is available for this variant.
  • SpliceAI returned no score, so the ordinary BP7 path's BP4 prerequisite cannot be evaluated; the missing score is not evidence of no splice impact.
  • No entry for c.2988C>T, p.Leu996=, or p.L996= was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No entry for c.2988C>T, p.Leu996=, or p.L996= was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No entry for c.2988C>T, p.Leu996=, or p.L996= was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No entry for c.2988C>T, p.Leu996=, or p.L996= was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗PMID:22505045 ↗
BP4 N/ANot applicable: p.Leu996 lies outside ENIGMA's aa 10-40 and aa 2481-3186 domains, so silent-variant BP4 does not apply. Details ▾Hide ▴
Reasoning

The ENIGMA BP4 scope includes silent variants only when they are inside a defined clinically important functional domain, or intronic variants outside canonical donor/acceptor positions. This synonymous exon 11 variant encodes p.Leu996=, outside the BRCA2 PALB2-binding domain (aa 10-40) and DNA-binding domain (aa 2481-3186), and is not intronic; BP4 is therefore not_applicable before evaluating the missing SpliceAI result.

VCEP rule
Silent variant inside a (potentially) clinically important functional domain, if no predicted impact via splicing (SpliceAI ≤0.1). ... Intronic variants outside of the donor and acceptor ±1,2 positions AND no predicted impact via splicing (SpliceAI ≤0.1). ... As justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA2 PALB2 binding domain aa 10-40; BRCA2 DNA binding aa 2481-3186.
Evidence considered
  • Case normalization identifies the variant as synonymous at p.Leu996= in exon 11.
  • ENIGMA defines BRCA2 clinically important functional domains as the PALB2 binding domain aa 10-40 and DNA binding aa 2481-3186.
  • The variant's amino-acid position 996 is outside both named BRCA2 domains; the intronic BP4 path is inapplicable because this is an exonic synonymous variant.
  • The governing VCEP files were searched for c.2988C>T, p.Leu996=, and p.L996=; no variant-specific pre-assigned BP4 code was found.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗

Statement

In silico

SpliceAI returned NO scores for this variant, so no SpliceAI-based splice prediction is available. This is missing data, NOT evidence of absent splice impact: it must not be used to support BP4 or to argue against PP3/PVS1. Pangolin scores may be present but are not calibrated for PP3/BP4 here.

7 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

  • Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
    No paper-specific finding is recorded.
    PMID 25741868 ↗
  • American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility.
    American Society of Clinical Oncology · 2003
    This paper is a general ASCO policy statement and does not mention BRCA2 c.2988C>T or p.(Leu996=); it provides no variant-specific case-control, phenotype, or classification evidence.
    Does not name this variant
    PMID 12692171 ↗
    Quoted passage
    ASCO recommends that genetic counseling and testing be offered when the 1) individual has personal or family history features suggestive of a genetic cancer susceptibility condition, 2) the genetic test can be adequately interpreted, and 3) the test results will aid in diagnosis or influence the medical or surgical management of the patient or family members at hereditary risk of cancer.

    Indications for Genetic Testing for Cancer Susceptibility

  • Risk assessment and genetic counseling for hereditary breast and ovarian cancer: recommendations of the National Society of Genetic Counselors.
    Berliner JL et al. · 2007
    This paper gives general hereditary breast and ovarian cancer genetic-counseling recommendations and does not provide variant-specific evidence for BRCA2 c.2988C>T or p.(Leu996=).
    Does not name this variant
    PMID 17508274 ↗
    Quoted passage
    These cancer genetic counseling recommendations describe the medical, psychosocial and ethical implications of identifying at-risk individuals for hereditary breast and ovarian cancer (HBOC) through cancer risk assessment, with or without genetic susceptibility testing.

    Abstract

  • American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility.
    Robson ME et al. · 2010
    This paper discusses BRCA1/2 testing generally but does not mention BRCA2 c.2988C>T or p.(Leu996=), and supplies no variant-specific case-control or pathogenic-report evidence.
    Does not name this variant
    PMID 20065170 ↗
    Quoted passage
    Potentially medically relevant DTC tests include tests with accepted clinical utility (eg, BRCA1/2 testing) and with uncertain clinical utility (eg, genomic profiling through SNP genotyping).

    DTC Availability of Genetic Tests

  • American Society of Clinical Oncology Policy Statement Update: Genetic and Genomic Testing for Cancer Susceptibility.
    This paper discusses inherited cancer susceptibility and BRCA2 generally, but does not explicitly mention BRCA2 c.2988C>T or p.(Leu996=), and provides no variant-specific phenotype, case-control, or classification evidence.
    Does not name this variant
    PMID 26324357 ↗
    Quoted passage
    Identifying inherited mutations in genes such as BRCA1, BRCA2, and the genes associated with Lynch syndrome allows for interventions that can significantly reduce the development of cancer and improve survival.

    Multigene Panel Testing, paragraph beginning “Identifying inherited mutations”

  • PMID 31479213
    No paper-specific finding is recorded.
    PMID 31479213 ↗
  • Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
    No paper-specific finding is recorded.
    PMID 28492532 ↗

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

gnomAD v4.1 1 / 1,613,732 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Captured SpliceAI source record Open source ↗
ClinVar 3 Likely benign Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗
ClinGen CSpec Captured ClinGen CSpec source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 6.19682e-07; MAF= 0.00006%, 1/1613732 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47532e-07; MAF= 0.00008%, 1/1179896 alleles, homozygotes = 0).

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Likely benign (3 clinical laboratories). (ClinVarID = 1159930)

In silico

SpliceAI returned NO scores for this variant, so no SpliceAI-based splice prediction is available. This is missing data, NOT evidence of absent splice impact: it must not be used to support BP4 or to argue against PP3/PVS1. Pangolin scores may be present but are not calibrated for PP3/BP4 here.

Functional

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.