Five-step scale from benign to pathogenic. This variant is likely benign. Select a step to read what it means.
This variantScenario
BenignPathogenic
Likely benign.A likely benign classification under the recorded framework.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
About BRCA2
BRCA2 encodes a DNA repair protein that maintains genome stability by repairing double-strand breaks through homologous recombination and by protecting DNA replication forks. It acts as a tumor suppressor, and inherited loss-of-function changes cause hereditary breast and ovarian cancer syndrome, with elevated lifetime risks of breast, ovarian, prostate, and pancreatic cancers; biallelic changes cause Fanconi anemia complementation group D1. Reduced or altered BRCA2 activity is implicated in multiple tumor types, and PARP inhibitors are an approved treatment for BRCA2-associated ovarian and breast cancers.
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.
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 3
BP4Supporting
BP4 · supporting
Met, supporting: SpliceAI maximum delta 0.003 is below the ENIGMA BP4 threshold of <=0.1 for this synonymous variant in the DNA-binding domain.
BP6Supporting
BP6 · supporting
Met, Supporting: exact ClinVar expert-panel classification is Likely benign, satisfying the requested BP6 rule.
BP7Supporting
BP7 · supporting
Met, supporting: the synonymous variant has SpliceAI maximum delta 0.003, satisfying BP4 and the ENIGMA BP7 requirement for silent variants.
Recorded classification: Likely benign
Likely Benign: ENIGMA BRCA2 Table 3 applies BP4, BP6, and BP7 at supporting benign strength, totaling -3 points.
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
25 / 1,614,148 alleles
gnomAD v4.1: 25 / 1,614,148 alleles. Recorded AF 1.5488e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.19347e-05; MAF= 0.00119%, 3/251368 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 6.15157e-05; MAF= 0.00615%, 1/16256 alleles, homozygotes = 0).
ACMG/AMP criteria under ClinGen BRCA2 VCEP v1.2, with the data and sources behind each one.
28 criteria with recorded statuses: 3 met · 3 not met · 12 not assessed · 10 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
For the requested consequence/LOF criteria, all three codes are not applicable under the governing ENIGMA BRCA1/2 v1.2 specification: the variant is synonymous, has unchanged protein length, and is not an in-frame indel or stop-loss variant.
The supplied VCEP files were searched under all three requested variant notations; no exact variant-level assignment was found.
For the requested codon/residue/domain criteria, the synonymous variant is not eligible for PS1, PM5, or PP2; PM1 is prohibited by the ENIGMA VCEP; and BP1 fails because residue 3132 is inside the BRCA2 DNA-binding domain.
The applicable VCEP rules outrank generic ACMG thresholds; no paper-level evidence was needed for these criterion determinations.
Only the requested phenotype/prevalence/assertion criteria were evaluated.
PS4, PP4, and BP5 remain not assessed because the governing variant-specific quantitative evidence was unavailable.
PP5 is not met because the exact expert-panel classification is Likely benign rather than Pathogenic/Likely pathogenic.
BP6 is met at Supporting strength under the requested exact-variant expert-panel rule.
Population criteria are not assessable under the governing ENIGMA BRCA2 v1.2 rules because the specified non-cancer gnomAD queries failed.
All-comers gnomAD observations are recorded as context but were not substituted for the VCEP-mandated non-cancer datasets.
No criteria match.
Met · 3
BP4SupportingMet, supporting: SpliceAI maximum delta 0.003 is below the ENIGMA BP4 threshold of <=0.1 for this synonymous variant in the DNA-binding domain.
Details ▾Hide ▴
Reasoning
The variant is synonymous (NM_000059.4:c.9396A>G; NP_000050.3:p.(Lys3132=)), so BP4 is evaluated through the ENIGMA BRCA2 SpliceAI path rather than REVEL. The governing ENIGMA BRCA2 V1.2 specification permits BP4 for a silent variant inside a clinically important functional domain when SpliceAI <=0.1. Lys3132 lies within the BRCA2 DNA-binding domain (amino acids 2481-3186), and the available SpliceAI scores are DS_AG 0.000, DS_AL 0.000, DS_DG 0.003, and DS_DL 0.000, with maximum delta 0.003. Because 0.003 <=0.1, BP4 Supporting is met. No variant-specific pre-assigned BP4 row was found in Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, or PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Rule
ENIGMA BRCA2 V1.2 BP4 Supporting: silent variant inside a clinically important functional domain with SpliceAI <=0.1.
Evidence considered
The ENIGMA BRCA2 V1.2 specification states that BP4 applies to a silent variant inside a clinically important functional domain when SpliceAI <=0.1; the BRCA2 DNA-binding domain is amino acids 2481-3186.
Lys3132 is within the BRCA2 DNA-binding domain.
SpliceAI returned DS_AG 0.000, DS_AL 0.000, DS_DG 0.003, and DS_DL 0.000; the maximum delta is 0.003.
Still missing
No variant-specific BP4 entry for c.9396A>G, p.Lys3132=, or p.K3132= was found in Specifications_V1.2_2024-11-18.docx.txt.
No variant-specific BP4 entry for c.9396A>G, p.Lys3132=, or p.K3132= was found in Appendices_V1.2_2024-11-18.docx.txt.
No variant-specific BP4 entry for c.9396A>G, p.Lys3132=, or p.K3132= was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
BP7SupportingMet, supporting: the synonymous variant has SpliceAI maximum delta 0.003, satisfying BP4 and the ENIGMA BP7 requirement for silent variants.
Details ▾Hide ▴
Reasoning
The variant is synonymous (NM_000059.4:c.9396A>G; NP_000050.3:p.(Lys3132=)), satisfying BP7 scope. ENIGMA BRCA2 V1.2 states that BP7 Supporting may be applied to a silent variant inside a clinically important functional domain if BP4 is met, and that BP7 is applied in addition to BP4 for a synonymous variant with no predicted splice impact. BP4 is met because the available SpliceAI maximum delta is 0.003, which is <=0.1. Therefore BP7 Supporting is met without adding any separate prediction or double-counting an independent computational result. No variant-specific pre-assigned BP7 row was found in Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, or PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Rule
ENIGMA BRCA2 V1.2 BP7 Supporting: synonymous variant inside a clinically important functional domain if BP4 is met; apply in addition to BP4.
Evidence considered
The ENIGMA BRCA2 V1.2 specification states that BP7 Supporting applies to silent variants inside a clinically important functional domain if BP4 is met, and is applied in addition to BP4 for synonymous variants.
The variant is synonymous and encodes p.(Lys3132=); the residue lies within the BRCA2 DNA-binding domain.
BP4 is met from SpliceAI maximum delta 0.003, below the <=0.1 no-impact threshold.
Still missing
No variant-specific BP7 entry for c.9396A>G, p.Lys3132=, or p.K3132= was found in Specifications_V1.2_2024-11-18.docx.txt.
No variant-specific BP7 entry for c.9396A>G, p.Lys3132=, or p.K3132= was found in Appendices_V1.2_2024-11-18.docx.txt.
No variant-specific BP7 entry for c.9396A>G, p.Lys3132=, or p.K3132= was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
PP3Not met: SpliceAI maximum delta 0.003 is below the ENIGMA PP3 threshold of >=0.2 for synonymous variants.
Details ▾Hide ▴
Reasoning
The variant is synonymous (NM_000059.4:c.9396A>G; NP_000050.3:p.(Lys3132=)), so PP3 is evaluated only through the ENIGMA BRCA2 SpliceAI path. The governing ENIGMA BRCA2 V1.2 specification requires SpliceAI >=0.2 for PP3 in silent variants. The case SpliceAI result is available with a maximum delta of 0.003 (DS_AG 0.000, DS_AL 0.000, DS_DG 0.003, DS_DL 0.000), which is below the VCEP threshold; therefore PP3 is not met. No variant-specific pre-assigned PP3 row was found in Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, or PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
PP5Not met: the exact ClinVar expert-panel classification is Likely benign, whereas PP5 requires Pathogenic or Likely pathogenic.
Details ▾Hide ▴
Reasoning
The exact ClinVar expert-panel classification is Likely benign, not Pathogenic or Likely pathogenic. The requested PP5 rule requires an exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification; ordinary laboratory submissions and aggregate labels cannot trigger PP5. ENIGMA's VCEP specification also states PP5 is not for use.
Rule
Apply supporting PP5 only for an exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification.
Evidence considered
ClinVar exact match NM_000059.4(BRCA2):c.9396A>G (p.Lys3132=) has one expert-panel classification of Likely benign.
The ClinVar record contains many ordinary laboratory submissions, but those are not eligible to trigger PP5.
BP1Not met: SpliceAI max delta 0.003 is permissive, but residue 3132 lies inside the excluded DNA-binding domain aa 2481-3186.
Details ▾Hide ▴
Reasoning
ENIGMA BRCA2 v1.2 permits BP1_Strong for silent substitutions outside a potentially clinically important functional domain and with SpliceAI ≤0.1. SpliceAI max delta is 0.003, satisfying the splicing condition, but p.Lys3132 lies within the BRCA2 DNA-binding domain aa 2481-3186, so the required outside-domain condition is not met.
Rule
ENIGMA BRCA2 v1.2 BP1_Strong: silent substitution outside a potentially clinically important functional domain AND SpliceAI ≤0.1.
Evidence considered
ENIGMA BRCA2 v1.2 BP1_Strong requires a silent substitution outside a potentially clinically important functional domain and no predicted splicing, defined as SpliceAI ≤0.1.
The variant is p.(Lys3132=), and the governing specification defines the BRCA2 DNA-binding domain as aa 2481-3186; residue 3132 is inside that domain.
SpliceAI max delta is 0.003, which is ≤0.1 and satisfies the no-predicted-splicing component, but the outside-domain requirement fails.
Still missing
No exact entry for c.9396A>G, p.Lys3132=, or p.K3132= was found in Specifications_V1.2_2024-11-18.docx.txt.
No exact entry for c.9396A>G, p.Lys3132=, or p.K3132= was found in Appendices_V1.2_2024-11-18.docx.txt.
No exact entry for c.9396A>G, p.Lys3132=, or p.K3132= was found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt.
PS3Not assessed: no variant-specific protein-function or combined mRNA/protein assay was found, and SpliceAI maximum delta 0.003 is not PS3 evidence.
Details ▾Hide ▴
Reasoning
The ENIGMA BRCA1/2 VCEP specification reserves PS3 for well-established protein-function assays or combined mRNA-and-protein assays and directs variant-specific calibrated assignments to Table 9. Searches of Specifications_Table9_V1.2_2024-11-18.xlsx.txt, HUMU-40-1557-s001.xlsx.txt, Specifications_V1.2_2024-11-18.docx.txt, and Appendices_V1.2_2024-11-18.docx.txt found no entry for c.9396A>G, p.Lys3132=, or p.K3132=. The case evidence contains no variant-specific protein-function or combined mRNA/protein assay result; SpliceAI prediction (maximum delta 0.003) is computational splicing evidence, not PS3 functional assay evidence. Therefore PS3 cannot be assigned.
Rule
ENIGMA BRCA2 V1.2 PS3: well-established in vitro or in vivo functional studies supportive of a damaging effect, measured via protein only or mRNA and protein combined; use calibrated variant-specific recommendations in Table 9.
Evidence considered
ENIGMA V1.2 states that PS3 functional-assay evidence must measure protein function alone or mRNA and protein together; mRNA-only assay evidence is handled under an alternative RNA code.
The governing Table 9 converted text was searched for c.9396A>G, p.Lys3132=, and p.K3132=; no exact variant row was found.
HUMU-40-1557-s001 converted text was searched for c.9396A>G, p.Lys3132=, and p.K3132=; no exact variant row was found.
The full Specifications V1.2 and Appendices V1.2 converted texts were searched for c.9396A>G, p.Lys3132=, and p.K3132=; no exact variant entry was found in either file.
The case reports SpliceAI maximum delta 0.003, but the VCEP framework does not treat a computational splice prediction as PS3 protein-function evidence.
Still missing
No exact variant entry was found in Specifications_Table9_V1.2_2024-11-18.xlsx.txt.
No exact variant entry was found in HUMU-40-1557-s001.xlsx.txt.
No exact variant entry was found in Specifications_V1.2_2024-11-18.docx.txt.
No exact variant entry was found in Appendices_V1.2_2024-11-18.docx.txt.
A variant-specific validated protein-function or combined mRNA/protein assay result is unavailable.
PS4Not assessed: no variant-specific case-control p-value, OR >=4, or confidence interval excluding 2.0 was available.
Details ▾Hide ▴
Reasoning
The ENIGMA BRCA2 specification requires case-control evidence with p-value <=0.05, OR >=4, and a lower confidence interval excluding 2.0. No variant-specific case-control counts, odds ratio, confidence interval, or p-value were found. The exact variant was not found in HUMU-40-1557-s001.xlsx or SupplementaryTables_V1.2_2024-11-18.xlsx; the latter's searchable full text is unavailable, which is a gap rather than evidence of absence. The exact variant was also absent from the reviewed candidate papers.
Rule
Case-control studies; p-value <=0.05 and OR >=4 (lower confidence interval excludes 2.0).
Evidence considered
ENIGMA specifies PS4 as case-control p-value <=0.05 and OR >=4, with the lower confidence interval excluding 2.0.
Searches of HUMU-40-1557-s001.xlsx found no c.9396A>G, p.Lys3132=, or p.K3132= entry.
SupplementaryTables_V1.2_2024-11-18.xlsx was declared governing for PS4, but its full text is unavailable and therefore remains an explicit evidence gap.
The reviewed candidate publications did not mention this exact variant or provide variant-specific PS4 data.
Still missing
No exact-variant entry was found in HUMU-40-1557-s001.xlsx after searching c.9396A>G, p.Lys3132=, and p.K3132=.
SupplementaryTables_V1.2_2024-11-18.xlsx full text is unavailable, so its ST7 entry could not be checked.
No variant-specific case-control p-value, odds ratio, or confidence interval was available in the case evidence or reviewed publications.
PM2Not assessed: required non-cancer absence is unknown, while all-comers gnomAD confirms presence at 3/251368 and 25/1614148 alleles.
Details ▾Hide ▴
Reasoning
The governing ENIGMA BRCA2 v1.2 permits PM2 at supporting strength only when the variant is absent from controls in gnomAD v2.1 non-cancer exomes and gnomAD v3.1 non-cancer, with regional mean read depth at least 25. Both required non-cancer queries failed and explicitly report unknown frequency, so absence cannot be established. The all-comers records show the variant present (3/251368 alleles in gnomAD v2.1 and 25/1614148 in gnomAD v4.1), but those records cannot substitute for the specified non-cancer sources. No exact variant entry was found in Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, or HUMU-40-1557-s001.xlsx.txt.
Rule
Absent from controls in an outbred population, from gnomAD v2.1 non-cancer exome-only subset and gnomAD v3.1 non-cancer; regional average read depth must be >=25. Apply at supporting strength only.
Evidence considered
ENIGMA BRCA2 v1.2 specifies PM2 supporting only when absent from gnomAD v2.1 non-cancer exomes and gnomAD v3.1 non-cancer, with regional average read depth at least 25.
The gnomAD v2.1 non-cancer and gnomAD v3.1 non-cancer queries failed and explicitly state that frequency is unknown, not absent.
All-comers gnomAD v2.1 contains 3 alternate alleles among 251368 (AF 1.19347e-05), and gnomAD v4.1 contains 25 among 1614148 (AF 1.5488e-05), demonstrating presence but not resolving the VCEP-required non-cancer assessment.
Still missing
GNOMAD_V2_1_NON_CANCER query failed; absence and required regional depth are unknown.
GNOMAD_V3_1_NON_CANCER query failed; absence and required regional depth are unknown.
No exact c.9396A>G, p.Lys3132=, or p.K3132= entry was found in Specifications_V1.2_2024-11-18.docx.txt.
No exact c.9396A>G, p.Lys3132=, or p.K3132= entry was found in Appendices_V1.2_2024-11-18.docx.txt.
No exact c.9396A>G, p.Lys3132=, or p.K3132= entry was found in HUMU-40-1557-s001.xlsx.txt.
PM3Not assessed: no Fanconi Anemia phenotype, pathogenic BRCA2 variant in trans, phase, or PM3 point-bearing proband observation is available.
Details ▾Hide ▴
Reasoning
The ENIGMA BRCA2 VCEP restricts PM3 to a patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia and a pathogenic or likely pathogenic co-occurring BRCA2 variant, with PM3 strength assigned from Table 6 points. The available case evidence contains no affected-proband Fanconi Anemia phenotype, chromosome-breakage result, pathogenic variant in trans or cis, parental phase, homozygous presentation, or PM3 point-bearing observation for NM_000059.4:c.9396A>G (p.Lys3132=). Therefore PM3 cannot be assigned from the available evidence.
Rule
Apply PM3 only for a patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia and a co-occurring pathogenic or likely pathogenic variant in the same gene; assign PM3_Supporting at 1 point, PM3 at 2 points, and PM3_Strong at 4 or more points.
Evidence considered
The ENIGMA VCEP specification limits PM3 to BRCA1/2-related Fanconi Anemia phenotype with a co-occurring pathogenic or likely pathogenic variant in the same gene and assigns PM3 from Table 6 points: Supporting 1 point, Moderate 2 points, and Strong at 4 or more points.
The case evidence contains no variant-specific Fanconi Anemia presentation, chromosome-breakage result, pathogenic BRCA2 variant in trans, parental phase, homozygous presentation, or PM3 point-bearing observation for NM_000059.4:c.9396A>G (p.Lys3132=).
Direct searches of Specifications_V1.2_2024-11-18.docx.txt for c.9396A>G, p.Lys3132=, and p.K3132= found no variant-specific entry.
Still missing
No affected-proband Fanconi Anemia phenotype, chromosome-breakage result, co-occurring pathogenic or likely pathogenic BRCA2 variant, parental phase, or quantitative PM3 point observation was found in the case evidence bundle.
No entry for c.9396A>G, p.Lys3132=, or p.K3132= was found when searching Specifications_V1.2_2024-11-18.docx.txt, the governing VCEP specification file.
PP1Not assessed: no segregation observations or quantitative LR are available, so the ENIGMA PP1 thresholds of 2.08, 4.3, 18.7, and 350 cannot be applied.
Details ▾Hide ▴
Reasoning
No variant-specific affected-family segregation observations, parental testing results, meioses, quantitative co-segregation likelihood ratio, or COOL/CAL-Leiden analysis were provided for NM_000059.4:c.9396A>G (p.Lys3132=). The ENIGMA VCEP permits PP1 only when quantitative co-segregation evidence reaches LR >=2.08:1 for supporting, >=4.3:1 for moderate, >=18.7:1 for strong, or >=350:1 for very strong evidence; no LR is available to assign a strength.
Rule
Apply PP1 only from quantitative co-segregation analysis: supporting LR >=2.08:1; moderate LR >=4.3:1; strong LR >=18.7:1; very strong LR >=350:1. LR >0.48 and <2.08 is non-informative in either direction.
Evidence considered
The case evidence bundle contains no variant-specific family, parental, meiosis, or segregation result for NM_000059.4:c.9396A>G (p.Lys3132=).
The ENIGMA specification requires quantitative co-segregation analysis and assigns 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; no LR is reported.
Direct searches of the converted HUMU-40-1557-s001.xlsx text found no c.9396A>G, p.Lys3132=, or p.K3132= entry.
The declared SupplementaryTables_V1.2.xlsx full text is unavailable after conversion failure, so its ST7 lookup cannot be treated as audited evidence.
Still missing
No affected-family segregation data, parental genotypes, meioses, or quantitative co-segregation LR were found in the case evidence bundle.
No entry for c.9396A>G, p.Lys3132=, or p.K3132= was found in HUMU-40-1557-s001.xlsx, the VCEP file governing BS4/PS4/S3/BS3/PM2.
SupplementaryTables_V1.2.xlsx is declared by the BRCA2 VCEP index as governing BS4/PS4, but its full text is unavailable because conversion failed; its ST7 posterior-probability lookup could not be audited.
PP4Not assessed: no exact-variant combined clinical LR was available for comparison with the PP4 supporting threshold LR >=2.08.
Details ▾Hide ▴
Reasoning
ENIGMA restricts PP4 to clinically calibrated multifactorial likelihood evidence. Its supporting threshold is LR >=2.08, moderate is LR >=4.3, strong is LR >=18.7, and very strong is LR >=350. No exact-variant record was found in PMID_31853058_BRCA2_clinical_history_LR.xlsx, and no combined clinical LR was supplied by the case evidence or the reviewed Easton/Parsons materials. Therefore no PP4 strength can be assigned.
Rule
PP4 Supporting: LR >=2.08:1; Moderate: LR >=4.3:1; Strong: LR >=18.7:1; Very Strong: LR >=350:1.
Evidence considered
ENIGMA defines PP4 as multifactorial clinical evidence and states the supporting comparison operator is LR >=2.08.
Searches of PMID_31853058_BRCA2_clinical_history_LR.xlsx and HUMU-40-1557-s001.xlsx found no exact-variant row under the supplied coding and protein notations.
Easton and Li sources provide methodology context only; neither supplied an exact-variant LR in the reviewed material.
Still missing
No exact-variant entry was found in PMID_31853058_BRCA2_clinical_history_LR.xlsx after searching c.9396A>G, p.Lys3132=, and p.K3132=.
No exact-variant entry was found in HUMU-40-1557-s001.xlsx after searching c.9396A>G, p.Lys3132=, and p.K3132=.
No combined multifactorial clinical LR was available from the case evidence.
BA1Not assessed: the VCEP-required non-cancer frequencies failed, so the BA1 threshold of FAF > 0.001 cannot be evaluated.
Details ▾Hide ▴
Reasoning
The governing ENIGMA BRCA2 v1.2 rule requires maximum FAF above 0.1% (FAF > 0.001) in gnomAD v2.1 non-cancer exomes and/or gnomAD v3.1 non-cancer non-founder populations. Both required non-cancer queries failed and provide unknown frequencies. The available all-comers gnomAD v2.1 and v4.1 frequencies (total AF 1.19347e-05 and 1.5488e-05; gnomAD v4.1 exome grpmax FAF 0.00016125) cannot replace the VCEP-mandated non-cancer sources. No exact variant entry was found in Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, or HUMU-40-1557-s001.xlsx.txt.
Rule
Filter allele frequency (FAF) is above 0.1% (FAF > 0.001) in gnomAD v2.1 (non-cancer, exome only subset) and/or gnomAD v3.1 (non-cancer), non-founder population(s).
Evidence considered
ENIGMA BRCA2 v1.2 specifies BA1 only when non-cancer FAF is above 0.001 in gnomAD v2.1 non-cancer exomes and/or gnomAD v3.1 non-cancer non-founder populations.
The gnomAD v2.1 non-cancer and gnomAD v3.1 non-cancer queries failed and explicitly report frequency as unknown, not absent or rare.
All-comers gnomAD v2.1 shows AF 1.19347e-05 (3/251368 alleles; homozygotes 0), while gnomAD v4.1 shows AF 1.5488e-05 (25/1614148 alleles; homozygotes 0) and exome grpmax FAF 0.00016125; these are not the VCEP-required non-cancer datasets.
Still missing
GNOMAD_V2_1_NON_CANCER query failed; required non-cancer exome FAF is unknown.
GNOMAD_V3_1_NON_CANCER query failed; required non-cancer genome FAF is unknown.
No exact c.9396A>G, p.Lys3132=, or p.K3132= entry was found in Specifications_V1.2_2024-11-18.docx.txt.
No exact c.9396A>G, p.Lys3132=, or p.K3132= entry was found in Appendices_V1.2_2024-11-18.docx.txt.
No exact c.9396A>G, p.Lys3132=, or p.K3132= entry was found in HUMU-40-1557-s001.xlsx.txt.
BS1Not assessed: the VCEP-required non-cancer frequencies failed, so the BS1 FAF thresholds of >0.00002 to 0.0001 cannot be evaluated.
Details ▾Hide ▴
Reasoning
The governing ENIGMA BRCA2 v1.2 rule requires non-cancer FAF above 0.00002 and at or below 0.0001 for supporting BS1, or above 0.0001 for strong BS1, in gnomAD v2.1 non-cancer exomes and/or gnomAD v3.1 non-cancer non-founder populations. Both required non-cancer queries failed. All-comers frequencies cannot be substituted, so BS1 cannot be assigned. No exact variant entry was found in Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, or HUMU-40-1557-s001.xlsx.txt.
Rule
Filter allele frequency (FAF) is above 0.01% (FAF > 0.0001) for strong BS1, or above 0.002% (FAF > 0.00002) and less than or equal to 0.01% (FAF <= 0.0001) for supporting BS1, in gnomAD v2.1 non-cancer exomes and/or gnomAD v3.1 non-cancer non-founder populations.
Evidence considered
ENIGMA BRCA2 v1.2 specifies BS1 using maximum FAF from gnomAD v2.1 non-cancer exomes and/or gnomAD v3.1 non-cancer non-founder populations: >0.0001 is strong and >0.00002 through 0.0001 is supporting.
The gnomAD v2.1 non-cancer and gnomAD v3.1 non-cancer queries failed and explicitly report frequency as unknown.
All-comers gnomAD v2.1 AF is 1.19347e-05 and gnomAD v4.1 AF is 1.5488e-05; these totals do not satisfy the VCEP source requirement for BS1 assessment.
Still missing
GNOMAD_V2_1_NON_CANCER query failed; required non-cancer exome FAF is unknown.
GNOMAD_V3_1_NON_CANCER query failed; required non-cancer genome FAF is unknown.
No exact c.9396A>G, p.Lys3132=, or p.K3132= entry was found in Specifications_V1.2_2024-11-18.docx.txt.
No exact c.9396A>G, p.Lys3132=, or p.K3132= entry was found in Appendices_V1.2_2024-11-18.docx.txt.
No exact c.9396A>G, p.Lys3132=, or p.K3132= entry was found in HUMU-40-1557-s001.xlsx.txt.
BS2Not assessed: gnomAD reports 0 homozygotes, but no healthy-adult observations or ENIGMA Table 8 point assignments are available for BS2.
Details ▾Hide ▴
Reasoning
The governing ENIGMA BRCA2 v1.2 applies BS2 from healthy-adult observations under Specifications Table 8, with point totals of at least 4 for strong, 2 for moderate, or 1 for supporting, and requires consideration of Fanconi Anemia features. The available gnomAD records report zero homozygotes but do not provide the required healthy-adult phenotype, age, phase, or Table 8 point assignments. No exact variant entry was found in Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, or HUMU-40-1557-s001.xlsx.txt.
Rule
Applied in absence of features of recessive disease, namely Fanconi Anemia phenotype; use Specifications Table 8 for additional stipulations and point assignment: BS2 >= 4 points strong, BS2 moderate = 2 points, BS2 supporting = 1 point.
Evidence considered
ENIGMA BRCA2 v1.2 requires BS2 scoring through Specifications Table 8: at least 4 points for strong, 2 points for moderate, or 1 point for supporting, with absence of Fanconi Anemia features considered.
gnomAD v2.1 reports 0 homozygotes among 251368 alleles and gnomAD v4.1 reports 0 homozygotes among 1614148 alleles, but homozygote absence alone is not the required healthy-adult BS2 evidence.
Still missing
No healthy-adult phenotype, age, genotype-phase, or ENIGMA Table 8 BS2 point data are available.
No exact c.9396A>G, p.Lys3132=, or p.K3132= entry was found in Specifications_V1.2_2024-11-18.docx.txt.
No exact c.9396A>G, p.Lys3132=, or p.K3132= entry was found in Appendices_V1.2_2024-11-18.docx.txt.
No exact c.9396A>G, p.Lys3132=, or p.K3132= entry was found in HUMU-40-1557-s001.xlsx.txt.
BS3Not assessed: no variant-specific benign protein-function or combined mRNA/protein assay was found, and SpliceAI maximum delta 0.003 cannot establish BS3.
Details ▾Hide ▴
Reasoning
The ENIGMA BRCA1/2 VCEP specification reserves BS3 for well-established protein-function assays or combined mRNA-and-protein assays showing no damaging effect and directs variant-specific calibrated assignments to Table 9. Searches of Specifications_Table9_V1.2_2024-11-18.xlsx.txt, HUMU-40-1557-s001.xlsx.txt, Specifications_V1.2_2024-11-18.docx.txt, and Appendices_V1.2_2024-11-18.docx.txt found no entry for c.9396A>G, p.Lys3132=, or p.K3132=. The case evidence contains no variant-specific benign protein-function or combined mRNA/protein assay result; SpliceAI prediction (maximum delta 0.003) cannot establish BS3. Therefore BS3 cannot be assigned.
Rule
ENIGMA BRCA2 V1.2 BS3: well-established in vitro or in vivo functional studies showing no damaging effect on protein function, measured via protein only or mRNA and protein combined; use calibrated variant-specific recommendations in Table 9.
Evidence considered
ENIGMA V1.2 states that BS3 functional-assay evidence must show no damaging effect on protein function, measured via protein alone or mRNA and protein together; mRNA-only assay evidence is handled under an alternative RNA code.
The governing Table 9 converted text was searched for c.9396A>G, p.Lys3132=, and p.K3132=; no exact variant row was found.
HUMU-40-1557-s001 converted text was searched for c.9396A>G, p.Lys3132=, and p.K3132=; no exact variant row was found.
The full Specifications V1.2 and Appendices V1.2 converted texts were searched for c.9396A>G, p.Lys3132=, and p.K3132=; no exact variant entry was found in either file.
The case reports SpliceAI maximum delta 0.003, but the VCEP framework does not treat a computational splice prediction as BS3 protein-function evidence.
Still missing
No exact variant entry was found in Specifications_Table9_V1.2_2024-11-18.xlsx.txt.
No exact variant entry was found in HUMU-40-1557-s001.xlsx.txt.
No exact variant entry was found in Specifications_V1.2_2024-11-18.docx.txt.
No exact variant entry was found in Appendices_V1.2_2024-11-18.docx.txt.
A variant-specific validated benign protein-function or combined mRNA/protein assay result is unavailable.
BS4Not assessed: no affected-relative non-segregation data or quantitative LR are available, so the ENIGMA BS4 thresholds of 0.48, 0.23, 0.05, and 0.00285 cannot be applied.
Details ▾Hide ▴
Reasoning
No variant-specific non-segregation observations, affected relatives who lacked the variant, family structure, meioses, quantitative co-segregation likelihood ratio, or COOL/CAL-Leiden analysis were provided for NM_000059.4:c.9396A>G (p.Lys3132=). The ENIGMA VCEP permits BS4 only when quantitative evidence supports lack of segregation, with BS4 Supporting at LR <=0.48, BS4 Moderate at LR <=0.23, BS4 Strong at LR <=0.05, and BS4 Very Strong at LR <=0.00285; no LR is available to assign a strength.
Rule
Apply BS4 only from quantitative lack-of-segregation analysis: supporting LR <=0.48:1; moderate LR <=0.23:1; strong LR <=0.05:1; very strong LR <=0.00285:1. LR >0.48 and <2.08 is non-informative in either direction.
Evidence considered
The case evidence bundle contains no variant-specific affected-relative non-segregation, parental, meiosis, or family-level result for NM_000059.4:c.9396A>G (p.Lys3132=).
The ENIGMA specification assigns BS4 Supporting at LR <=0.48:1, BS4_Moderate at LR <=0.23:1, BS4 at LR <=0.05:1, and BS4_Very Strong at LR <=0.00285:1; no LR is reported.
Direct searches of the converted HUMU-40-1557-s001.xlsx text found no c.9396A>G, p.Lys3132=, or p.K3132= entry.
The declared SupplementaryTables_V1.2.xlsx full text is unavailable after conversion failure, so its ST7 lookup cannot be treated as audited evidence.
Still missing
No affected-family non-segregation data, family structure, parental genotypes, meioses, or quantitative co-segregation LR were found in the case evidence bundle.
No entry for c.9396A>G, p.Lys3132=, or p.K3132= was found in HUMU-40-1557-s001.xlsx, the VCEP file governing BS4/PS4/S3/BS3/PM2.
SupplementaryTables_V1.2.xlsx is declared by the BRCA2 VCEP index as governing BS4/PS4, but its full text is unavailable because conversion failed; its ST7 posterior-probability lookup could not be audited.
BP5Not assessed: no exact-variant clinical LR was available for comparison with the BP5 supporting inequality LR <=0.48.
Details ▾Hide ▴
Reasoning
ENIGMA restricts BP5 to a combined multifactorial clinical LR against pathogenicity. The exact criterion-specific operators are LR <=0.48 for supporting, LR <=0.23 for moderate, LR <=0.05 for strong, and LR <=0.00285 for very strong. No exact-variant clinical-history or multifactorial LR was found in PMID_31853058_BRCA2_clinical_history_LR.xlsx, HUMU-40-1557-s001.xlsx, or the reviewed publications, so no explicit inequality can be completed and BP5 cannot be assigned.
Rule
BP5 Supporting: LR <=0.48 to >0.23:1; Moderate: LR <=0.23:1; Strong: LR <=0.05:1; Very Strong: LR <=0.00285:1.
Evidence considered
ENIGMA states BP5 Supporting requires LR <=0.48; this direction was read from the BP5 rule itself, not inferred from PP4.
Searches of PMID_31853058_BRCA2_clinical_history_LR.xlsx and HUMU-40-1557-s001.xlsx found no exact-variant row under the supplied coding and protein notations.
Easton and Li sources provide methodology context only and no exact-variant LR for this assessment.
Still missing
No exact-variant entry was found in PMID_31853058_BRCA2_clinical_history_LR.xlsx after searching c.9396A>G, p.Lys3132=, and p.K3132=.
No exact-variant entry was found in HUMU-40-1557-s001.xlsx after searching c.9396A>G, p.Lys3132=, and p.K3132=.
No combined multifactorial LR against pathogenicity was available from the case evidence or reviewed publications.
Not applicable · 10· recorded as not applicableShow reasons ▾Hide reasons ▴PVS1N/ANot applicable: c.9396A>G is synonymous, with SpliceAI max delta 0.003 and no qualifying null or canonical splice consequence for PVS1.
Details ▾Hide ▴
Reasoning
NM_000059.4:c.9396A>G is a synonymous coding variant, annotated as NP_000050.3:p.(Lys3132=) / p.(K3132=), so it does not create a nonsense, frameshift, canonical splice-site, initiation-codon, or exon-deletion loss-of-function allele. The ENIGMA BRCA2 specification limits PVS1 to null variants and transcript-level RNA evidence of a damaging splice consequence; the BRCA2 Table 4 entry for exon 25 covers null and canonical splice-site categories, not this synonymous substitution. SpliceAI max delta is 0.003, providing no evidence of a splice-mediated loss-of-function consequence. Therefore PVS1 is not applicable, with no PVS1 strength assigned.
Rule
ENIGMA BRCA2 v1.2 PVS1 null-variant/RNA framework; synonymous substitutions without demonstrated damaging splicing are outside PVS1 applicability.
Evidence considered
ENIGMA BRCA2 v1.2 defines PVS1 for null variants including nonsense, frameshift, canonical +/-1,2 splice-site, initiation-codon, and exon-deletion variants, with RNA-based PVS1 reserved for demonstrated damaging transcript effects.
Specifications Table 4 places c.9257-c.9501 in BRCA2 exon 25 and lists PVS1/PTC and canonical splice-site decision entries; c.9396A>G is a synonymous substitution within that exon and is not one of those null categories.
The case evidence annotates NM_000059.4:c.9396A>G as synonymous with NP_000050.3:p.(Lys3132=) / p.(K3132=), and SpliceAI reports max delta 0.003.
The exact variant notations c.9396A>G, p.Lys3132=, and p.K3132= were searched in all four supplied governing full-text files; no exact entry was found.
Still missing
No exact c.9396A>G, p.Lys3132=, or p.K3132= entry was found in Specifications_V1.2_2024-11-18.docx.txt.
No exact c.9396A>G, p.Lys3132=, or p.K3132= entry was found in Appendices_V1.2_2024-11-18.docx.txt.
No exact c.9396A>G, p.Lys3132=, or p.K3132= entry was found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt.
No exact c.9396A>G, p.Lys3132=, or p.K3132= entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
PS1N/ANot applicable: the variant is synonymous, and SpliceAI max delta 0.003 provides no predicted splice event for PS1 comparison.
Details ▾Hide ▴
Reasoning
The variant is synonymous, NM_000059.4:c.9396A>G, p.(Lys3132=), not a missense substitution. ENIGMA BRCA2 v1.2 limits the protein-change form of PS1 to a variant producing the same missense substitution as a previously established pathogenic or likely pathogenic variant; its alternative PS1 form requires a precisely matching predicted splicing event. SpliceAI max delta is 0.003, indicating no predicted splice impact, and no governing VCEP table entry was found for c.9396A>G, p.Lys3132=, or p.K3132=.
Rule
ENIGMA BRCA2 v1.2 PS1: same missense substitution as a known pathogenic/likely pathogenic variant, or the same predicted splicing event; synonymous variant with no predicted splice impact does not qualify.
Evidence considered
The case normalization identifies NM_000059.4:c.9396A>G as synonymous, encoding NP_000050.3:p.(Lys3132=) / p.(K3132=).
ENIGMA BRCA2 v1.2 specifies PS1 for the same missense substitution as a previously established pathogenic variant, or for a precisely matching predicted splicing event; the variant is synonymous rather than missense.
SpliceAI max delta is 0.003, below the ENIGMA no-predicted-splicing threshold of 0.1, so there is no predicted splice event to match.
The three declared searchable VCEP files were searched for c.9396A>G, p.Lys3132=, and p.K3132=; no exact entry was found.
Still missing
No exact entry for c.9396A>G, p.Lys3132=, or p.K3132= was found in Specifications_V1.2_2024-11-18.docx.txt.
No exact entry for c.9396A>G, p.Lys3132=, or p.K3132= was found in Appendices_V1.2_2024-11-18.docx.txt.
No exact entry for c.9396A>G, p.Lys3132=, or p.K3132= was found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt.
PS2VCEPNot applicable: the ENIGMA VCEP explicitly prohibits PS2 for BRCA1/2 because de novo occurrences are not calibrated for these relatively common cancers.
Details ▾Hide ▴
Reasoning
The ENIGMA BRCA1/2 VCEP specification explicitly says PS2 is not to be used for BRCA1/2-related cancers because these cancers occur relatively commonly and there is no information to calibrate the predictive capacity of de novo occurrences. This criterion is therefore not applicable regardless of whether parental testing or paternity confirmation is available.
VCEP rule
Do not use PS2 for BRCA1/2-related cancers.
Evidence considered
Specifications V1.2 Table 1 states for PS2: "Do not use" because BRCA1/2-related cancers occur relatively commonly and there is no information to calibrate the predictive capacity of de novo occurrences.
PM1VCEPNot applicable: ENIGMA explicitly prohibits PM1, despite residue 3132 lying within the stated DNA-binding interval aa 2481-3186.
Details ▾Hide ▴
Reasoning
The governing ENIGMA BRCA2 v1.2 specification explicitly marks PM1 as Do not use and states that hotspot or functional-domain information is considered within PP3/BP4 instead. The residue is p.Lys3132=, within the specification's BRCA2 DNA-binding interval aa 2481-3186, but that domain location does not override the VCEP's PM1 prohibition. vcep_materials.json has no gene entry under domain_tables.
VCEP rule
ENIGMA BRCA2 v1.2 PM1: Do not use; hotspot and functional-domain information is considered as part of PP3/BP4.
Evidence considered
ENIGMA BRCA2 v1.2 Table 1 marks PM1 as Do not use and directs hotspot/domain information to the bioinformatic PP3/BP4 framework.
The specification defines the BRCA2 DNA-binding domain as amino acids 2481-3186; residue 3132 is inside this interval, but domain membership cannot activate a criterion the VCEP has prohibited.
The authoritative vcep_materials.json domain_tables object contains no BRCA2 entry; no alternate extracted domain list supersedes the governing specification.
The three declared searchable VCEP files were searched for c.9396A>G, p.Lys3132=, and p.K3132=; no exact entry was found.
Still missing
No exact entry for c.9396A>G, p.Lys3132=, or p.K3132= was found in Specifications_V1.2_2024-11-18.docx.txt.
No exact entry for c.9396A>G, p.Lys3132=, or p.K3132= was found in Appendices_V1.2_2024-11-18.docx.txt.
No exact entry for c.9396A>G, p.Lys3132=, or p.K3132= was found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt.
PM4VCEPNot applicable: the synonymous p.(Lys3132=) change causes no protein-length change, whereas ENIGMA PM4 is restricted to in-frame indels or stop-loss variants.
Details ▾Hide ▴
Reasoning
The ENIGMA BRCA1/2 specification explicitly marks PM4 as not used and defines it only for protein-length changes caused by in-frame insertions/deletions in a non-repeat region or stop-loss variants. NM_000059.4:c.9396A>G is synonymous, p.(Lys3132=), and leaves protein length unchanged; it is neither an in-frame indel nor a stop-loss variant. PM4 is therefore not applicable.
VCEP rule
ENIGMA BRCA1/2 v1.2 PM4: do not use; limited to protein-length changes from specified in-frame indels or stop-loss variants.
Evidence considered
ENIGMA BRCA1/2 v1.2 states that PM4 is not used and describes the criterion as protein-length changes from in-frame insertions/deletions in a non-repeat region or stop-loss variants.
The case annotation is synonymous, NP_000050.3:p.(Lys3132=) / p.(K3132=), so the encoded protein length is unchanged.
The exact variant notations c.9396A>G, p.Lys3132=, and p.K3132= were searched in the governing ENIGMA specification and appendices; no exact entry was found.
Still missing
No exact c.9396A>G, p.Lys3132=, or p.K3132= entry was found in Specifications_V1.2_2024-11-18.docx.txt.
No exact c.9396A>G, p.Lys3132=, or p.K3132= entry was found in Appendices_V1.2_2024-11-18.docx.txt.
PM5N/ANot applicable: p.Lys3132= is synonymous, whereas ENIGMA PM5 is not used for missense and PM5 (PTC) requires a termination-codon variant.
Details ▾Hide ▴
Reasoning
The variant is synonymous, not a missense change. ENIGMA BRCA2 v1.2 marks the ordinary missense PM5 as Do not use and repurposes PM5 only as PM5 (PTC) for protein-termination-codon variants annotated with PVS1. This variant does not create a termination codon and is not a PVS1 null variant; therefore neither PM5 form applies.
Rule
ENIGMA BRCA2 v1.2 PM5: ordinary missense PM5 is not used; PM5 (PTC) is restricted to PVS1 protein-termination-codon variants.
Evidence considered
The case normalization identifies the consequence as synonymous, encoding p.(Lys3132=).
ENIGMA BRCA2 v1.2 marks ordinary PM5 as Do not use and defines PM5 (PTC) only for a protein termination codon variant in an exon with a different proven pathogenic PTC variant, as additional weight for PVS1.
Specifications Table 4 was searched; its PM5 entries are exon-level PTC guidance and contain no exact entry for this synonymous variant.
The three declared searchable VCEP files were searched for c.9396A>G, p.Lys3132=, and p.K3132=; no exact entry was found.
Still missing
No exact entry for c.9396A>G, p.Lys3132=, or p.K3132= was found in Specifications_V1.2_2024-11-18.docx.txt.
No exact entry for c.9396A>G, p.Lys3132=, or p.K3132= was found in Appendices_V1.2_2024-11-18.docx.txt.
No exact entry for c.9396A>G, p.Lys3132=, or p.K3132= was found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt.
PM6VCEPNot applicable: the ENIGMA VCEP explicitly prohibits PM6 for BRCA1/2 because uncalibrated de novo occurrences cannot support this criterion.
Details ▾Hide ▴
Reasoning
The ENIGMA BRCA1/2 VCEP specification explicitly says PM6 is not to be used for BRCA1/2-related cancers because these cancers occur relatively commonly and there is no information to calibrate the predictive capacity of de novo occurrences without confirmed paternity and maternity. This criterion is therefore not applicable.
VCEP rule
Do not use PM6 for BRCA1/2-related cancers.
Evidence considered
Specifications V1.2 Table 1 states for PM6: "Do not use" because BRCA1/2-related cancers occur relatively commonly and there is no information to calibrate the predictive capacity of de novo occurrences.
PP2VCEPNot applicable: ENIGMA marks PP2 as Not Applicable, and the variant is synonymous rather than missense.
Details ▾Hide ▴
Reasoning
The governing ENIGMA BRCA2 v1.2 specification explicitly marks PP2 as Not Applicable. The variant is also synonymous, whereas PP2 is a missense-gene mechanism criterion; no generic PP2 evidence can override the applicable VCEP rule.
VCEP rule
ENIGMA BRCA2 v1.2 PP2: Not Applicable.
Evidence considered
ENIGMA BRCA2 v1.2 explicitly marks PP2 as Not Applicable.
The variant consequence is synonymous, not missense, so the generic PP2 concept is not applicable independently of the VCEP rule.
BP2VCEPNot applicable: the ENIGMA VCEP explicitly says BP2 is not to be used and limits it to the context of BS2.
Details ▾Hide ▴
Reasoning
The governing ENIGMA BRCA1/2 VCEP specification explicitly states that BP2 is not to be used and is applied only in the context of BS2. BP2 therefore cannot be assigned for this BRCA2 variant under the governing framework, regardless of any unquantified cis or trans co-occurrence observation.
VCEP rule
Do not use BP2 under the ENIGMA BRCA1/2 VCEP specification; the specification states that BP2 is applied only in the context of BS2.
Evidence considered
Specifications V1.2 Table 1 states for BP2: "Do not use" and "Applied only in the context of BS2."
Direct searches of Specifications_V1.2_2024-11-18.docx.txt for c.9396A>G, p.Lys3132=, and p.K3132= found no variant-specific entry.
Still missing
No entry for c.9396A>G, p.Lys3132=, or p.K3132= was found when searching Specifications_V1.2_2024-11-18.docx.txt, the governing VCEP specification file.
BP3VCEPNot applicable: c.9396A>G is a synonymous single-nucleotide substitution, not an in-frame deletion or insertion required by the ENIGMA BP3 rule.
Details ▾Hide ▴
Reasoning
The ENIGMA BRCA1/2 specification explicitly marks BP3 as not used and defines it only for in-frame deletions/insertions in a repetitive region without a known function. NM_000059.4:c.9396A>G is a synonymous single-nucleotide substitution, p.(Lys3132=), not an in-frame deletion or insertion; repeat-region context therefore cannot make BP3 applicable. BP3 is not applicable.
VCEP rule
ENIGMA BRCA1/2 v1.2 BP3: do not use; limited to in-frame deletions/insertions in repetitive regions without known function.
Evidence considered
ENIGMA BRCA1/2 v1.2 marks BP3 as not used and defines it only for in-frame deletions/insertions in a repetitive region without a known function.
The case annotation is the synonymous substitution NM_000059.4:c.9396A>G, NP_000050.3:p.(Lys3132=) / p.(K3132=), not an in-frame deletion or insertion.
The exact variant notations c.9396A>G, p.Lys3132=, and p.K3132= were searched in the governing ENIGMA specification and appendices; no exact entry was found.
Still missing
No exact c.9396A>G, p.Lys3132=, or p.K3132= entry was found in Specifications_V1.2_2024-11-18.docx.txt.
No exact c.9396A>G, p.Lys3132=, or p.K3132= entry was found in Appendices_V1.2_2024-11-18.docx.txt.
AF 1.5e-05 · 25 / 1,614,148 alleles · 0 hom · FAF 8.1e-05
Middle Eastern2 / 6,062
0.00033
African/African American11 / 75,062
0.00015
Remaining individuals5 / 62,504
8e-05
South Asian2 / 91,080
2.2e-05
European (non-Finnish)5 / 1,179,990
4.2e-06
0 alternate alleles recorded in 5 other groups: Admixed American, European (Finnish), Amish, East Asian, Ashkenazi Jewish.
gnomAD v2.1
AF 1.2e-05 · 3 / 251,368 alleles · 0 hom
African/African American1 / 16,256
6.2e-05
South Asian1 / 30,614
3.3e-05
European (non-Finnish)1 / 113,680
8.8e-06
0 alternate alleles recorded in 5 other groups: Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.5488e-05; MAF= 0.00155%, 25/1614148 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.000329924; MAF= 0.03299%, 2/6062 alleles, homozygotes = 0); grpmax FAF= 8.139e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.19347e-05; MAF= 0.00119%, 3/251368 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 6.15157e-05; MAF= 0.00615%, 1/16256 alleles, homozygotes = 0).
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
SpliceAI and Pangolin
SpliceAI acceptor lossat -139 bp
0.000
SpliceAI acceptor gainat -112 bp
0.000
SpliceAI donor lossat +105 bp
0.000
SpliceAI donor gainat -1 bp
0.003
Pangolin splice lossmagnitude shown
-0.002
Pangolin splice gain
0.009
Other predictors
REVEL
Not available
BayesDel
Not available
How the predictions were used
BP4SupportingMet, supporting: SpliceAI maximum delta 0.003 is below the ENIGMA BP4 threshold of <=0.1 for this synonymous variant in the DNA-binding domain.
Details ▾Hide ▴
Reasoning
The variant is synonymous (NM_000059.4:c.9396A>G; NP_000050.3:p.(Lys3132=)), so BP4 is evaluated through the ENIGMA BRCA2 SpliceAI path rather than REVEL. The governing ENIGMA BRCA2 V1.2 specification permits BP4 for a silent variant inside a clinically important functional domain when SpliceAI <=0.1. Lys3132 lies within the BRCA2 DNA-binding domain (amino acids 2481-3186), and the available SpliceAI scores are DS_AG 0.000, DS_AL 0.000, DS_DG 0.003, and DS_DL 0.000, with maximum delta 0.003. Because 0.003 <=0.1, BP4 Supporting is met. No variant-specific pre-assigned BP4 row was found in Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, or PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Rule
ENIGMA BRCA2 V1.2 BP4 Supporting: silent variant inside a clinically important functional domain with SpliceAI <=0.1.
Evidence considered
The ENIGMA BRCA2 V1.2 specification states that BP4 applies to a silent variant inside a clinically important functional domain when SpliceAI <=0.1; the BRCA2 DNA-binding domain is amino acids 2481-3186.
Lys3132 is within the BRCA2 DNA-binding domain.
SpliceAI returned DS_AG 0.000, DS_AL 0.000, DS_DG 0.003, and DS_DL 0.000; the maximum delta is 0.003.
Still missing
No variant-specific BP4 entry for c.9396A>G, p.Lys3132=, or p.K3132= was found in Specifications_V1.2_2024-11-18.docx.txt.
No variant-specific BP4 entry for c.9396A>G, p.Lys3132=, or p.K3132= was found in Appendices_V1.2_2024-11-18.docx.txt.
No variant-specific BP4 entry for c.9396A>G, p.Lys3132=, or p.K3132= was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
BP7SupportingMet, supporting: the synonymous variant has SpliceAI maximum delta 0.003, satisfying BP4 and the ENIGMA BP7 requirement for silent variants.
Details ▾Hide ▴
Reasoning
The variant is synonymous (NM_000059.4:c.9396A>G; NP_000050.3:p.(Lys3132=)), satisfying BP7 scope. ENIGMA BRCA2 V1.2 states that BP7 Supporting may be applied to a silent variant inside a clinically important functional domain if BP4 is met, and that BP7 is applied in addition to BP4 for a synonymous variant with no predicted splice impact. BP4 is met because the available SpliceAI maximum delta is 0.003, which is <=0.1. Therefore BP7 Supporting is met without adding any separate prediction or double-counting an independent computational result. No variant-specific pre-assigned BP7 row was found in Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, or PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Rule
ENIGMA BRCA2 V1.2 BP7 Supporting: synonymous variant inside a clinically important functional domain if BP4 is met; apply in addition to BP4.
Evidence considered
The ENIGMA BRCA2 V1.2 specification states that BP7 Supporting applies to silent variants inside a clinically important functional domain if BP4 is met, and is applied in addition to BP4 for synonymous variants.
The variant is synonymous and encodes p.(Lys3132=); the residue lies within the BRCA2 DNA-binding domain.
BP4 is met from SpliceAI maximum delta 0.003, below the <=0.1 no-impact threshold.
Still missing
No variant-specific BP7 entry for c.9396A>G, p.Lys3132=, or p.K3132= was found in Specifications_V1.2_2024-11-18.docx.txt.
No variant-specific BP7 entry for c.9396A>G, p.Lys3132=, or p.K3132= was found in Appendices_V1.2_2024-11-18.docx.txt.
No variant-specific BP7 entry for c.9396A>G, p.Lys3132=, or p.K3132= was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
PP3Not met: SpliceAI maximum delta 0.003 is below the ENIGMA PP3 threshold of >=0.2 for synonymous variants.
Details ▾Hide ▴
Reasoning
The variant is synonymous (NM_000059.4:c.9396A>G; NP_000050.3:p.(Lys3132=)), so PP3 is evaluated only through the ENIGMA BRCA2 SpliceAI path. The governing ENIGMA BRCA2 V1.2 specification requires SpliceAI >=0.2 for PP3 in silent variants. The case SpliceAI result is available with a maximum delta of 0.003 (DS_AG 0.000, DS_AL 0.000, DS_DG 0.003, DS_DL 0.000), which is below the VCEP threshold; therefore PP3 is not met. No variant-specific pre-assigned PP3 row was found in Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, or PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
8 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
ACOG Practice Bulletin No. 103: Hereditary breast and ovarian cancer syndrome.
2009
The paper discusses BRCA2 hereditary cancer biology but does not mention c.9396A>G or p.(K3132=) and provides no variant-specific PS4, PP4, BP5, PP5, or BP6 evidence.
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.
Richards S et al. · 2015
The paper provides general ACMG/AMP guidance and does not report this exact BRCA2 variant or variant-specific PS4/PP4/BP5 evidence.
The variant classification approach described in this article is meant to be applicable to variants in all Mendelian genes
Methods, scope of the variant-classification approach
A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mende
The paper does not mention this exact BRCA2 variant and offers only general cohort-level observations about benign synonymous variants, not variant-specific evidence.
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= 1.5488e-05; MAF= 0.00155%, 25/1614148 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.000329924; MAF= 0.03299%, 2/6062 alleles, homozygotes = 0); grpmax FAF= 8.139e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.19347e-05; MAF= 0.00119%, 3/251368 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 6.15157e-05; MAF= 0.00615%, 1/16256 alleles, homozygotes = 0).
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Likely benign (11 clinical laboratories) and as Benign (2 clinical laboratories) and as Uncertain significance (1 clinical laboratory) and as Likely Benign (1 clinical laboratory) and as likely benign (1 clinical laboratory) and as Likely benign by Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) (expert panel). (ClinVarID = 184747)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
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.
This variant was interpreted by pipeline 8.0.0.
The current version is 11.0.07.
Re-running queues a fresh interpretation; the result replaces this page when complete.
Re-runs are not free. Blank draws on today's public interpretation allowance; with a code, it uses one of that code's uses.