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
BS1Supporting
BS1 · supporting
Met at Supporting: gnomAD v3.1 non-cancer genome grpmax FAF 6.803e-05 falls between the ENIGMA BS1 Supporting limits >2e-05 and <=1e-04.
BP1Strong
BP1 · strong
Met, Strong: synonymous residue 389 is outside BRCA2 domains aa 10-40 and 2481-3186, with SpliceAI max delta 0.001 versus the ≤0.1 threshold.
BP6Supporting
BP6 · supporting
Met, Supporting: the exact variant has a ClinVar 3-star ENIGMA expert-panel classification of Likely benign.
Recorded classification: Likely benign
Likely Benign: BS1 Supporting, BP1 Strong benign, and BP6 Supporting benign total -6 under the ENIGMA BRCA2 point system.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
The gnomAD v2.1 query FAILED for this variant, so its frequency in v2.1 is UNKNOWN. This is missing data, NOT evidence of absence or rarity, and must not support PM2 or any frequency-based criterion.
ACMG/AMP criteria under ClinGen BRCA2 VCEP v1.2, with the data and sources behind each one.
28 criteria with recorded statuses: 3 met · 6 not met · 9 not assessed · 10 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
The queried BRCA2 variant is a synonymous exon-10 substitution, NM_000059.4:c.1167G>A, encoding p.(Pro389=).
ENIGMA V1.2 governs this assessment: PVS1 is restricted to null consequences, while PM4 and BP3 are explicitly not applicable; none of the three requested criteria is met.
The queried variant is synonymous, p.(Pro389=)/p.(P389=), so classic missense residue criteria PS1 and PM5 do not apply; ENIGMA also explicitly excludes PM1 and PP2.
BP1_Strong is met under the governing ENIGMA rule because residue 389 is outside both approved BRCA2 functional domains and SpliceAI max delta is 0.001.
This group evaluated only PP3, BP4, and BP7 using the synonymous-variant SpliceAI path; REVEL was not used.
The governing ENIGMA BRCA2 v1.2 specification was applied before generic thresholds, and no exact variant entry was found in the three supplied full-text files.
For this synonymous BRCA2 c.1167G>A (p.Pro389=; p.P389=) variant, the governing ENIGMA VCEP population rules require non-cancer exome/genome datasets and separate exome/genome FAF evaluation.
The population evidence supports BS1 at Supporting because gnomAD v3.1 non-cancer genome grpmax FAF is 6.803e-05, while BA1 is not met because this is below 0.001.
PM2 is not met because the variant is observed in both required non-cancer population sources; BS2 is not assessed because gnomAD homozygotes are explicitly excluded from ENIGMA BS2 scoring and no qualifying phenotyped individual-level data are available.
No criteria match.
Met · 3
BS1SupportingMet at Supporting: gnomAD v3.1 non-cancer genome grpmax FAF 6.803e-05 falls between the ENIGMA BS1 Supporting limits >2e-05 and <=1e-04.
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Reasoning
The ENIGMA BRCA1/2 VCEP specification assigns BS1 Supporting when FAF is >0.00002 and <=0.0001 in gnomAD non-founder populations, considering exome and genome data separately. The gnomAD v3.1 non-cancer genome record reports grpmax FAF 6.803e-05, which falls within that interval; the gnomAD v2.1 non-cancer exome FAF 1.969e-05 is just below the Supporting lower bound. The genome value independently meets BS1 Supporting. No variant-specific BS1 pre-assignment 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
ENIGMA BS1 Supporting: FAF >0.00002 and <=0.0001 in gnomAD v2.1 non-cancer exomes and/or gnomAD v3.1 non-cancer genomes, considering exome and genome data separately.
Evidence considered
ENIGMA specifies BS1 Supporting for FAF >0.00002 and <=0.0001 in non-founder gnomAD populations, with exome and genome data assessed separately.
The gnomAD v3.1 non-cancer genome record reports grpmax FAF 6.803e-05, meeting the ENIGMA BS1 Supporting interval.
The gnomAD v2.1 non-cancer exome FAF is 1.969e-05, below the BS1 Supporting lower bound; the qualifying evidence is the v3.1 non-cancer genome value.
A directly consulted paper reports the corresponding legacy P389P synonymous variant in 6/793 Korean breast cancer patients and 0/167 normal controls; this is corroborative population context, not the governing VCEP frequency dataset.
Still missing
No variant-specific BS1 entry was found in Specifications_V1.2_2024-11-18.docx.txt.
No variant-specific BS1 entry was found in Appendices_V1.2_2024-11-18.docx.txt.
No variant-specific BS1 entry was found in HUMU-40-1557-s001.xlsx.txt.
BP1StrongMet, Strong: synonymous residue 389 is outside BRCA2 domains aa 10-40 and 2481-3186, with SpliceAI max delta 0.001 versus the ≤0.1 threshold.
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Reasoning
ENIGMA BRCA2 v1.2 assigns BP1_Strong to silent substitutions outside a potentially clinically important functional domain when no splicing is predicted. The variant is synonymous at residue 389, outside the approved BRCA2 PALB2-binding domain aa 10-40 and DNA-binding domain aa 2481-3186. SpliceAI max delta is 0.001, satisfying the VCEP SpliceAI ≤0.1 no-splicing threshold. The VCEP specification identifies BP1_Strong as combining variant type, domain position, and splicing prediction.
Rule
ENIGMA BRCA2 v1.2 BP1_Strong: silent substitution outside a potentially clinically important functional domain AND no predicted splicing, SpliceAI ≤0.1; missense prediction is not applicable.
Evidence considered
ENIGMA BRCA2 v1.2 specifies BP1_Strong for silent substitutions outside a potentially clinically important functional domain with SpliceAI ≤0.1.
Residue 389 is outside the VCEP-approved BRCA2 PALB2-binding domain aa 10-40 and DNA-binding domain aa 2481-3186.
SpliceAI max delta is 0.001, below the governing VCEP threshold of 0.1.
The specification states that BP1_Strong combines variant type, domain position, and splicing prediction.
BP6SupportingMet, Supporting: the exact variant has a ClinVar 3-star ENIGMA expert-panel classification of Likely benign.
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Reasoning
Expert panel Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) classified as Likely benign.
Rule
BP6 Supporting: exact-variant ClinVar expert-panel classification is Benign or Likely benign.
Evidence considered
ClinVar identifies the exact transcript variant NM_000059.4(BRCA2):c.1167G>A (p.Pro389=), variation 184355, with review status reviewed by expert panel and classification Likely benign by ENIGMA.
BP6 was applied only from the exact-variant expert-panel classification; ordinary laboratory submissions and aggregate ClinVar labels were not used.
PM2Not met: the variant is present in gnomAD v2.1 non-cancer exomes at AF 3.81942e-05 and gnomAD v3.1 non-cancer genomes at AF 6.75941e-05.
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Reasoning
The ENIGMA BRCA1/2 VCEP specification defines PM2 Supporting as absence from an outbred population in gnomAD v2.1 non-cancer exomes and gnomAD v3.1 non-cancer genomes, with adequate local read depth. This variant is observed in both required population sources: gnomAD v2.1 non-cancer exomes reports AF 3.81942e-05 (9/235638 alleles), and gnomAD v3.1 non-cancer genomes reports AF 6.75941e-05 (10/147942 alleles), with zero homozygotes in both records. Because the variant is present, PM2 is not met. No variant-specific PM2 pre-assignment 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
ENIGMA PM2 Supporting: absent from gnomAD v2.1 non-cancer exomes and gnomAD v3.1 non-cancer genomes, with average local read depth >=25.
Evidence considered
ENIGMA specifies PM2 Supporting only when absent from gnomAD v2.1 non-cancer exomes and gnomAD v3.1 non-cancer genomes, with local read depth >=25.
The variant is present in gnomAD v2.1 non-cancer exomes at AF 3.81942e-05, 9/235638 alleles, with zero homozygotes.
The variant is present in gnomAD v3.1 non-cancer genomes at AF 6.75941e-05, 10/147942 alleles, with zero homozygotes; therefore it is not absent from controls.
Still missing
No variant-specific PM2 entry was found in Specifications_V1.2_2024-11-18.docx.txt.
No variant-specific PM2 entry was found in Appendices_V1.2_2024-11-18.docx.txt.
No variant-specific PM2 entry was found in HUMU-40-1557-s001.xlsx.txt.
PP3Not met: SpliceAI maximum delta 0.001 is below the ENIGMA PP3 threshold of 0.2 for silent variants.
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Reasoning
The variant is synonymous (NM_000059.4:c.1167G>A; NP_000050.3:p.(Pro389=)), so the applicable computational path is SpliceAI rather than REVEL. SpliceAI is available and its maximum delta score is 0.001, below the ENIGMA BRCA2 PP3 splice-prediction threshold of 0.2; therefore PP3 is not met. The governing ENIGMA specification states that PP3 may be applied to silent variants when SpliceAI is at least 0.2. No exact variant entry was found when searching Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, or PMID_22505045_Houdayer_2012_HumMutat.pdf.txt for c.1167G>A, p.Pro389=, and p.P389=.
Rule
ENIGMA BRCA2 v1.2 PP3: predicted splicing with SpliceAI ≥0.2 for silent variants.
Evidence considered
The case normalization identifies NM_000059.4:c.1167G>A as synonymous, encoding NP_000050.3:p.(Pro389=); REVEL is therefore not the applicable path.
SpliceAI reports DS_AG 0.0, DS_AL 0.0, DS_DG 0.001, and DS_DL 0.0, with maximum delta 0.001.
ENIGMA BRCA2 Specifications v1.2 states: apply PP3 for predicted splicing (SpliceAI ≥0.2) for silent variants.
The exact-variant searches found no entry in the three governing full-text files.
Still missing
No exact c.1167G>A, p.Pro389=, or p.P389= entry was found in Specifications_V1.2_2024-11-18.docx.txt.
No exact c.1167G>A, p.Pro389=, or p.P389= entry was found in Appendices_V1.2_2024-11-18.docx.txt.
No exact c.1167G>A, p.Pro389=, or p.P389= entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
PP5Not met: the exact-variant ClinVar expert panel classified c.1167G>A as Likely benign, not Pathogenic or Likely pathogenic.
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Reasoning
The ENIGMA BRCA2 specification states that PP5 is not applicable for this VCEP. In addition, the exact-variant ClinVar expert-panel classification is Likely benign, not Pathogenic or Likely pathogenic, so it cannot support pathogenic PP5 under the requested expert-panel rule. Ordinary laboratory submissions and aggregate labels were not used.
Rule
PP5 applies only when an exact-variant ClinVar expert panel classifies the variant as Pathogenic or Likely pathogenic; otherwise it is not met.
Evidence considered
The ENIGMA BRCA2 specification marks PP5 as not applicable for this VCEP.
ClinVar exact variant NM_000059.4(BRCA2):c.1167G>A (p.Pro389=) has a 3-star expert-panel classification of Likely benign by ENIGMA; this is opposite to the pathogenic direction required for PP5.
Clinical-laboratory submissions and aggregate ClinVar labels were not used to trigger PP5.
BA1Not met: maximum applicable non-cancer FAF is 6.803e-05, below the ENIGMA BA1 threshold of >0.001.
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Reasoning
The ENIGMA BRCA1/2 VCEP specification sets BA1 at filter allele frequency >0.001 (0.1%) in gnomAD non-founder populations, evaluated separately by exome and genome data. The maximum applicable non-cancer values are gnomAD v2.1 non-cancer exomes FAF 1.969e-05 (0.001969%) and gnomAD v3.1 non-cancer genomes grpmax FAF 6.803e-05 (0.006803%), both below 0.001. Therefore BA1 is not met. No variant-specific BA1 pre-assignment 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
ENIGMA BA1: FAF >0.001 in gnomAD v2.1 non-cancer exomes and/or gnomAD v3.1 non-cancer genomes, considering exome and genome data separately.
Evidence considered
ENIGMA specifies BA1 at FAF >0.001 (0.1%) using maximum filter allele frequency in non-founder gnomAD populations, with exome and genome data considered separately.
The case evidence reports gnomAD v2.1 non-cancer exomes FAF 1.969e-05 and gnomAD v3.1 non-cancer genomes grpmax FAF 6.803e-05; neither reaches 0.001.
The queried synonymous variant is present in gnomAD v2.1 non-cancer exomes at AF 3.81942e-05 with 9/235638 alleles and zero homozygotes.
Still missing
No variant-specific BA1 entry was found in Specifications_V1.2_2024-11-18.docx.txt.
No variant-specific BA1 entry was found in Appendices_V1.2_2024-11-18.docx.txt.
No variant-specific BA1 entry was found in HUMU-40-1557-s001.xlsx.txt.
BP4Not met: SpliceAI maximum delta 0.001 is below 0.1, but ENIGMA BP4 requires a silent variant inside a clinically important BRCA2 domain.
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Reasoning
The variant is synonymous (NM_000059.4:c.1167G>A; NP_000050.3:p.(Pro389=)), so the applicable computational path is SpliceAI rather than REVEL. SpliceAI maximum delta is 0.001, numerically below the ENIGMA no-splicing threshold of 0.1, but ENIGMA v1.2 restricts computational BP4 for silent variants to those inside a potentially clinically important functional domain. Pro389 is outside the BRCA2 PALB2-binding domain (aa 10-40) and DNA-binding domain (aa 2481-3186), so the governing BP4 rule is not satisfied. No exact variant entry was found when searching Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, or PMID_22505045_Houdayer_2012_HumMutat.pdf.txt for c.1167G>A, p.Pro389=, and p.P389=.
Rule
ENIGMA BRCA2 v1.2 BP4: for silent variants, SpliceAI ≤0.1 and location inside a potentially clinically important functional domain.
Evidence considered
The case normalization identifies NM_000059.4:c.1167G>A as synonymous at protein position Pro389; REVEL is not applicable.
SpliceAI reports maximum delta 0.001, which is ≤0.1, but this numerical result does not override the VCEP's domain requirement.
ENIGMA BRCA2 Specifications v1.2 defines the relevant domains as PALB2 binding aa 10-40 and DNA binding aa 2481-3186; Pro389 lies outside both.
The exact-variant searches found no entry in the three governing full-text files.
Still missing
No exact c.1167G>A, p.Pro389=, or p.P389= entry was found in Specifications_V1.2_2024-11-18.docx.txt.
No exact c.1167G>A, p.Pro389=, or p.P389= entry was found in Appendices_V1.2_2024-11-18.docx.txt.
No exact c.1167G>A, p.Pro389=, or p.P389= entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
BP7Not met: Pro389 lies outside ENIGMA's qualifying domains, and no mRNA-only assay supports the alternative BP7_Strong route.
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Reasoning
The variant is synonymous, so BP7 is within criterion scope. However, ENIGMA v1.2 computational BP7 requires a silent variant inside a potentially clinically important functional domain and BP4 met; Pro389 is outside the BRCA2 PALB2-binding domain (aa 10-40) and DNA-binding domain (aa 2481-3186), so that supporting BP7 route is unavailable. The alternative BP7_Strong (RNA) route requires a well-established mRNA-only functional assay, and no such assay is present in the available evidence. No exact variant entry was found when searching Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, or PMID_22505045_Houdayer_2012_HumMutat.pdf.txt for c.1167G>A, p.Pro389=, and p.P389=.
Rule
ENIGMA BRCA2 v1.2 BP7: silent variant inside a potentially clinically important functional domain if BP4 is met; BP7_Strong (RNA) requires an mRNA-only functional assay.
Evidence considered
The case normalization identifies NM_000059.4:c.1167G>A as a synonymous p.(Pro389=) variant.
ENIGMA BRCA2 Specifications v1.2 requires computational BP7 for silent variants to be inside a potentially clinically important functional domain and requires BP4 to be met.
Pro389 is outside the ENIGMA BRCA2 PALB2-binding domain aa 10-40 and DNA-binding domain aa 2481-3186.
No well-established mRNA-only functional assay for this variant is present in the available evidence.
The exact-variant searches found no entry in the three governing full-text files.
Still missing
No exact c.1167G>A, p.Pro389=, or p.P389= entry was found in Specifications_V1.2_2024-11-18.docx.txt.
No exact c.1167G>A, p.Pro389=, or p.P389= entry was found in Appendices_V1.2_2024-11-18.docx.txt.
No exact c.1167G>A, p.Pro389=, or p.P389= entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
PS3Not assessed: no calibrated damaging functional assay was reported for c.1167G>A (p.Pro389=), and SpliceAI max delta 0.001 is not PS3 evidence.
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Reasoning
The ENIGMA BRCA1/2 VCEP specification reserves PS3 for well-established in vitro or in vivo studies showing a damaging protein effect, using protein-only assays or assays combining mRNA and protein, and directs reviewers to calibrated results in Table 9. The exact variant was not found in Specifications_Table9_V1.2_2024-11-18.xlsx under c.1167G>A, p.Pro389=, or p.P389=, nor under the equivalent legacy notation c.1395G>A or p.P389P. The other governing files likewise contain no variant-specific calibrated functional result for this synonymous change. PMID:17100994 reports the legacy synonymous variant P389P in a screening cohort but explicitly provides no functional assay. SpliceAI max delta 0.001 is computational splice prediction, not evidence of a damaging protein effect, and therefore cannot establish PS3. Available evidence is insufficient to assess PS3.
Rule
ENIGMA BRCA1/2 VCEP v1.2: PS3 applies to well-established in vitro or in vivo functional studies supportive of a damaging effect when the assay measures protein function alone or mRNA and protein together; use calibrated published assay recommendations in Table 9.
Evidence considered
The ENIGMA VCEP rule states that PS3 requires well-established functional studies showing a damaging effect and that protein-only or combined mRNA/protein assays are evaluated using calibrated Table 9 recommendations.
The full Table 9 text has no row for c.1167G>A, p.Pro389=, p.P389=, c.1395G>A, or p.P389P.
The full Specifications and Appendices texts contain the governing PS3 framework but no variant-specific calibrated assay result for this variant.
The full HUMU-40-1557-s001 text contains no row for this variant and no variant-specific functional assay result.
PMID:17100994 reports legacy BRCA2 1395G>A/P389P in Table 2 but states no functional assay was performed for the variant.
SpliceAI reports a maximum delta of 0.001; this is a computational splice prediction and does not establish a damaging protein-function assay result for PS3.
Still missing
No variant-specific PS3 entry was found in Specifications_Table9_V1.2_2024-11-18.xlsx after searching c.1167G>A, p.Pro389=, p.P389=, c.1395G>A, and p.P389P.
No variant-specific calibrated PS3 evidence was found in Specifications_V1.2_2024-11-18.docx.
No variant-specific calibrated PS3 evidence was found in Appendices_V1.2_2024-11-18.docx.
No variant-specific functional assay result was found in HUMU-40-1557-s001.xlsx.
PS4Not assessed: 6/793 cases versus 0/167 controls was reported, but the required PS4 p-value, OR >=4, and lower confidence limit excluding 2.0 are unavailable.
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Reasoning
The ENIGMA BRCA2 specification requires PS4 Strong for a case-control study with p-value <=0.05, odds ratio (OR) >=4, and a lower confidence-limit excluding 2.0. The exact synonymous variant is reported in PMID:17100994 under the legacy notation 1395G>A/P389P in 6 of 793 Korean breast-cancer patients and 0 of 167 controls, but that report does not provide the required p-value, OR, or confidence interval. The available data therefore cannot be checked against every governing PS4 requirement without deriving statistics not supplied by the governing record. The three VCEP files searched for c.1167G>A, p.Pro389=, and p.P389= contained no variant-level PS4 assignment; the SupplementaryTables_V1.2.xlsx full-text conversion is unavailable.
Rule
PS4 Strong: case-control p-value <=0.05 and OR >=4, with the lower confidence interval excluding 2.0.
Evidence considered
The ENIGMA BRCA2 specification states: "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. Case-control studies; p-value <=0.05 and OR >=4 (lower confidence interval excludes 2.0)."
PMID:17100994 reports legacy BRCA2 1395G>A/P389P in 6 of 793 sporadic breast-cancer patients and none of 167 normal controls, but supplies no p-value, odds ratio, or confidence interval for this variant.
The required exact-variant searches of Specifications_V1.2_2024-11-18.docx, HUMU-40-1557-s001.xlsx, and PMID_31853058_BRCA2_clinical_history_LR.xlsx found no c.1167G>A, p.Pro389=, or p.P389= entry; SupplementaryTables_V1.2.xlsx full text is unavailable.
Still missing
Specifications_V1.2_2024-11-18.docx: no exact-variant PS4 assignment found for c.1167G>A, p.Pro389=, or p.P389=.
HUMU-40-1557-s001.xlsx: no exact-variant entry found for c.1167G>A, p.Pro389=, or p.P389=.
PMID_31853058_BRCA2_clinical_history_LR.xlsx: no exact HGVS_Nucleotide entry found for BRCA2 c.1167G>A.
SupplementaryTables_V1.2.xlsx: full-text conversion unavailable, so its ST7 lookup could not be searched.
PM3Not assessed: no documented Fanconi anemia phenotype, same-gene pathogenic variant, or phase information is available to satisfy the ENIGMA PM3 rule.
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Reasoning
The ENIGMA BRCA2 VCEP specification restricts PM3 to patients with a phenotype consistent with BRCA1/2-related Fanconi anemia and a co-occurrent pathogenic or likely pathogenic variant in the same gene. The available case evidence documents no Fanconi anemia phenotype, no pathogenic BRCA2 variant in trans or in cis, no homozygous presentation, and no phase information for NM_000059.4:c.1167G>A (p.Pro389=). PMID:17100994 reports the synonymous variant as P389P in affected individuals but provides no phase, co-occurrence, or Fanconi anemia observations. Therefore, the required allelic evidence cannot be assessed rather than being inferred absent.
Rule
ENIGMA BRCA2 VCEP PM3: apply only in a patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi anemia and a co-occurrent pathogenic or likely pathogenic variant in the same gene; PM3_Supporting = 1 point, PM3 = 2 points, PM3_Strong = 4 or more points.
Evidence considered
ENIGMA BRCA2 Specification V1.2 states that PM3 applies only for a Fanconi anemia-consistent patient with co-occurrent pathogenic or likely pathogenic variants in the same gene; PM3 strength is assigned from Table 6 points (supporting 1, moderate 2, strong at least 4).
The case evidence contains no documented BRCA2 pathogenic co-variant, trans/cis phase, homozygous state, or Fanconi anemia phenotype for this variant.
PMID:17100994 reports the legacy synonymous notation 1395G>A/P389P in 6 of 793 Korean patients and none of 167 controls, but reports no phase, co-occurrence, or Fanconi anemia data.
Still missing
No c.1167G>A, p.Pro389=, or p.P389= entry was found when Specifications_V1.2_2024-11-18.docx.txt was searched; this is a VCEP-file search gap, not evidence that allelic observations are absent.
No case-level documentation establishes Fanconi anemia phenotype, a pathogenic or likely pathogenic BRCA2 co-variant, phase, or homozygosity.
PP1Not assessed: no quantitative co-segregation LR or affected-relative meioses are available to reach the ENIGMA PP1 threshold of LR >=2.08.
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Reasoning
No quantitative co-segregation likelihood ratio, meiosis count, pedigree-level genotype/phenotype data, or documented co-segregation across multiple affected relatives is available for this variant. The ENIGMA rule requires quantitative co-segregation analysis: PP1 supporting at LR >=2.08, moderate at LR >=4.3, strong at LR >=18.7, and very strong at LR >=350. The reviewed variant reports describe case/control observations without segregation analysis and therefore cannot establish PP1.
Rule
PP1 variable weight: quantitative co-segregation LR >=2.08 supporting, >=4.3 moderate, >=18.7 strong, or >=350 very strong; LR between 0.48 and 2.08 is not informative.
Evidence considered
ENIGMA BRCA1/2 Specification v1.2, Table 1: apply PP1 by quantitative co-segregation Bayes score, with supporting LR >=2.08, moderate LR >=4.3, strong LR >=18.7, and very strong LR >=350.
Han et al. (PMID:17100994) reports the synonymous P389P variant in 6 of 793 Korean sporadic breast cancer patients and none of 167 controls, but reports no segregation analysis or family meioses.
Kim et al. (PMID:16949048) reports the synonymous P389P variant in 3 of 1020 Korean breast cancer patients and 3 of 167 unaffected controls, but reports no segregation analysis or family meioses.
Still missing
No family pedigree with affected/unaffected phenotypes and variant genotypes was provided.
No quantitative co-segregation LR or meiosis count was provided.
HUMU-40-1557-s001.xlsx was searched for c.1167G>A, p.Pro389=, and p.P389=; no exact entry was found.
PP4Not assessed: no exact BRCA2 c.1167G>A combined clinical-history LR was found for comparison with the PP4 threshold >=2.08.
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Reasoning
The ENIGMA BRCA2 specification restricts PP4 to combined multifactorial clinical likelihood evidence and requires LR >=2.08 for Supporting, >=4.3 for Moderate, >=18.7 for Strong, or >=350 for Very Strong; LR values between >0.48 and <2.08 are non-informative. The governing PMID_31853058_BRCA2_clinical_history_LR.xlsx file was searched for exact BRCA2 c.1167G>A and no row was found, and no other case-level combined clinical LR is provided. The cited Easton and Li papers are methodology/context sources and cannot supply a variant-specific LR absent an exact row.
Rule
PP4: combined multifactorial clinical LR >=2.08 for Supporting, >=4.3 for Moderate, >=18.7 for Strong, or >=350 for Very Strong; LR >0.48 and <2.08 is non-informative.
Evidence considered
The ENIGMA BRCA2 specification states that PP4 is used only for combined LR toward pathogenicity and assigns Supporting at LR >=2.08, Moderate at LR >=4.3, Strong at LR >=18.7, and Very Strong at LR >=350; combined LR >0.48 and <2.08 is non-informative.
The exact BRCA2 c.1167G>A search in PMID_31853058_BRCA2_clinical_history_LR.xlsx found no variant-level clinical-history LR row.
Li et al. and Easton et al. were reviewed as methodology/context sources; neither supplies an exact-variant LR for this case in the available evidence.
Still missing
PMID_31853058_BRCA2_clinical_history_LR.xlsx: no exact Gene=BRCA2 and HGVS_Nucleotide=c.1167G>A row found.
No variant-specific combined multifactorial LR is available in the case evidence for PP4.
BS2Not assessed: gnomAD records show 0 homozygotes, but ENIGMA excludes frequency-dataset homozygotes and provides no qualifying phenotyped individual-level BS2 points.
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Reasoning
The ENIGMA BS2 rule requires phenotyped clinical or research-cohort individuals who are homozygous, or who carry the variant in the specified co-occurrence configurations, are cancer-unaffected or have late cancer onset, and lack Fanconi Anemia features; points are then summed to assign BS2 strength. The available evidence documents zero homozygotes in gnomAD v2.1 non-cancer data and zero homozygotes in gnomAD v3.1 non-cancer data, but ENIGMA explicitly excludes frequency-dataset homozygotes from BS2 scoring. No qualifying phenotyped individual-level BS2 observation or point total is available, so BS2 cannot be assessed.
Rule
ENIGMA BS2: use only qualifying phenotyped individuals and assign strength from summed Table 8 points; do not score gnomAD frequency-dataset homozygotes.
Evidence considered
ENIGMA Table 8 assigns BS2 from points in phenotyped individuals and states that homozygotes observed in gnomAD are not used for BS2 because frequency-based evidence is captured by BA1 or BS1.
The case evidence reports zero homozygotes in the gnomAD v2.1 non-cancer exome record and zero homozygotes in the gnomAD v3.1 non-cancer genome record.
No qualifying clinical-cohort individual-level observation and no BS2 point total are available.
Still missing
No qualifying phenotyped clinical or research-cohort BS2 observation with age, cancer status, phase, and Fanconi Anemia assessment was identified.
No variant-specific BS2 entry was found in Specifications_V1.2_2024-11-18.docx.txt.
No variant-specific BS2 entry was found in Appendices_V1.2_2024-11-18.docx.txt.
No variant-specific BS2 entry was found in HUMU-40-1557-s001.xlsx.txt.
BS3Not assessed: no calibrated benign functional assay was reported for c.1167G>A (p.Pro389=), and SpliceAI max delta 0.001 is not BS3 evidence.
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Reasoning
The ENIGMA BRCA1/2 VCEP specification reserves BS3 for well-established in vitro or in vivo studies showing no damaging effect on protein function, using protein-only assays or assays combining mRNA and protein; mRNA-only evidence for a silent variant is handled under the alternative BP7 framework. The exact variant was not found in Specifications_Table9_V1.2_2024-11-18.xlsx under c.1167G>A, p.Pro389=, or p.P389=, nor under the equivalent legacy notation c.1395G>A or p.P389P. The other governing files likewise contain no variant-specific calibrated functional result. PMID:17100994 reports the legacy synonymous variant P389P in a screening cohort but no functional assay. SpliceAI max delta 0.001 is not a validated no-damage protein assay and cannot establish BS3. Available evidence is insufficient to assess BS3.
Rule
ENIGMA BRCA1/2 VCEP v1.2: BS3 applies to well-established in vitro or in vivo functional studies showing no damaging effect on protein function when the assay measures protein function alone or mRNA and protein together; mRNA-only silent-variant evidence is handled under BP7.
Evidence considered
The ENIGMA VCEP rule states that BS3 requires well-established functional studies showing no damaging effect on protein function and that protein-only or combined mRNA/protein assays are evaluated using calibrated Table 9 recommendations.
The ENIGMA framework states that mRNA-only results for silent variants are assigned under the alternative BP7 pathway rather than BS3.
The full Table 9 text has no row for c.1167G>A, p.Pro389=, p.P389=, c.1395G>A, or p.P389P.
The full Specifications and Appendices texts contain the governing BS3 framework but no variant-specific calibrated assay result for this variant.
The full HUMU-40-1557-s001 text contains no row for this variant and no variant-specific functional assay result.
PMID:17100994 reports legacy BRCA2 1395G>A/P389P in Table 2 but states no functional assay was performed for the variant.
SpliceAI reports a maximum delta of 0.001; this is a computational splice prediction and does not establish a no-damage protein-function assay result for BS3.
Still missing
No variant-specific BS3 entry was found in Specifications_Table9_V1.2_2024-11-18.xlsx after searching c.1167G>A, p.Pro389=, p.P389=, c.1395G>A, and p.P389P.
No variant-specific calibrated BS3 evidence was found in Specifications_V1.2_2024-11-18.docx.
No variant-specific calibrated BS3 evidence was found in Appendices_V1.2_2024-11-18.docx.
No variant-specific functional assay result was found in HUMU-40-1557-s001.xlsx.
BS4Not assessed: no quantitative non-segregation LR or affected-relative genotype data are available to reach the ENIGMA BS4 threshold of LR <=0.48.
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Reasoning
No quantitative lack-of-segregation likelihood ratio, pedigree-level genotype/phenotype data, or documented non-segregation in affected relatives is available for this variant. The ENIGMA rule requires quantitative co-segregation analysis: BS4 supporting at LR <=0.48, moderate at LR <=0.23, strong at LR <=0.05, and very strong at LR <=0.00285. The reviewed variant reports describe case/control observations without family non-segregation analysis and therefore cannot establish BS4.
Rule
BS4 variable weight: quantitative lack-of-segregation LR <=0.48 supporting, <=0.23 moderate, <=0.05 strong, or <=0.00285 very strong.
Evidence considered
ENIGMA BRCA1/2 Specification v1.2, Table 1: apply BS4 by quantitative co-segregation Bayes score, with supporting LR <=0.48, moderate LR <=0.23, strong LR <=0.05, and very strong LR <=0.00285.
Han et al. (PMID:17100994) reports P389P in affected and control cohorts but no affected-family non-segregation analysis.
Kim et al. (PMID:16949048) reports P389P in breast cancer patients and unaffected controls but no affected-family non-segregation analysis.
The declared ENIGMA SupplementaryTables_V1.2.xlsx conversion is unavailable in full text, so its potential ST7 variant-level result could not be independently searched.
Still missing
No family pedigree with affected/unaffected phenotypes and variant genotypes was provided.
No quantitative non-segregation LR or meiosis count was provided.
SupplementaryTables_V1.2.xlsx, which declares BS4 and PS4, has no converted full text available; this is a source-conversion gap, not evidence that the file is empty.
SupplementaryTables_V1.2.xlsx was therefore not searchable for the variant's ST7 posterior/LR entry.
HUMU-40-1557-s001.xlsx was searched for c.1167G>A, p.Pro389=, and p.P389=; no exact entry was found.
BP5Not assessed: no exact BRCA2 c.1167G>A clinical-history LR was available for the BP5 comparison LR <=0.48.
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Reasoning
The ENIGMA BRCA2 specification permits BP5 only for a combined multifactorial clinical LR against pathogenicity and requires the criterion-specific downward comparisons: LR <=0.48 for Supporting, <=0.23 for Moderate, <=0.05 for Strong, or <=0.00285 for Very Strong. The governing PMID_31853058_BRCA2_clinical_history_LR.xlsx file was searched for exact BRCA2 c.1167G>A and no row was found, so no LR can be substituted into an explicit inequality. The exact-variant ClinVar Likely benign expert-panel classification is not a BP5 clinical-history LR and cannot establish BP5.
Rule
BP5: combined multifactorial clinical LR <=0.48 for Supporting, <=0.23 for Moderate, <=0.05 for Strong, or <=0.00285 for Very Strong.
Evidence considered
The ENIGMA BRCA2 specification states BP5 Supporting requires LR <=0.48, Moderate requires LR <=0.23, Strong requires LR <=0.05, and Very Strong requires LR <=0.00285; these are downward comparisons specific to BP5.
The exact BRCA2 c.1167G>A search in PMID_31853058_BRCA2_clinical_history_LR.xlsx found no variant-level clinical-history LR row, so no substituted inequality can be evaluated.
The ClinVar expert-panel Likely benign label is not a combined clinical-history LR and was not used as BP5.
Still missing
PMID_31853058_BRCA2_clinical_history_LR.xlsx: no exact Gene=BRCA2 and HGVS_Nucleotide=c.1167G>A row found.
No variant-specific combined multifactorial LR is available for BP5.
Not applicable · 10· recorded as not applicableShow reasons ▾Hide reasons ▴PVS1N/ANot applicable: c.1167G>A is synonymous, p.Pro389=, and is outside ENIGMA's PVS1 null-variant categories.
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Reasoning
NM_000059.4:c.1167G>A is a synonymous substitution in BRCA2 exon 10, annotated as NP_000050.3:p.(Pro389=)/p.(P389=). It does not create a nonsense or frameshift change, alter protein length, or occur at a canonical +/-1,2 splice site; therefore it is outside the ENIGMA BRCA2 PVS1 null-variant decision tree. The ENIGMA specification defines PVS1 for null variants and directs silent variants to the splicing-specific benign framework rather than PVS1. No exact c.1167G>A, p.Pro389=, or p.P389= entry 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; this is not needed to resolve the criterion because the governing consequence rule is explicit.
Rule
ENIGMA BRCA2 V1.2 PVS1 applies to null variants; a synonymous exon-10 substitution is not a PVS1-eligible consequence.
Evidence considered
Variant normalization confirms NM_000059.4:c.1167G>A produces NP_000050.3:p.(Pro389=)/p.(P389=), with variant consequence synonymous and exon 10 localization.
ENIGMA BRCA2 Version 1.2 Table 1 limits PVS1 to null variants including nonsense, frameshift, canonical +/-1,2 splice-site, initiation-codon, and exon-deletion variants.
The ENIGMA Table 4 PVS1 decision table covers initiation, nonsense/frameshift, deletion, duplication, and canonical splice-site variants; it has no applicable synonymous-variant PVS1 row.
The governing VCEP files were searched for c.1167G>A, p.Pro389=, and p.P389=; no exact variant entry was found.
Still missing
No exact c.1167G>A, p.Pro389=, or p.P389= entry was found in Specifications_V1.2_2024-11-18.docx.txt.
No exact c.1167G>A, p.Pro389=, or p.P389= entry was found in Appendices_V1.2_2024-11-18.docx.txt.
No exact c.1167G>A, p.Pro389=, or p.P389= entry was found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt.
No exact c.1167G>A, p.Pro389=, or p.P389= entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
PS1N/ANot applicable: the synonymous p.(P389=) variant has no established pathogenic same-missense or identical-splice-event comparator, and SpliceAI max delta is 0.001.
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Reasoning
The variant is synonymous, NM_000059.4:c.1167G>A, p.(Pro389=)/p.(P389=), rather than a missense substitution. ENIGMA BRCA2 v1.2 specifies PS1 for a predicted missense substitution matching a previously classified pathogenic missense variant, or for an identical predicted splice event. The governing VCEP full-text files were searched for c.1167G>A, p.Pro389=, p.P389=, and residue 389; no exact entry for this variant was found in Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, or Specifications_Table4_V1.2_2024-11-18.xlsx.txt. The case has no established pathogenic same-missense comparator and SpliceAI max delta is 0.001, so the missense or splice-event PS1 pathways do not apply.
Rule
ENIGMA BRCA2 v1.2 PS1 applies to a predicted missense substitution matching a pathogenic/likely pathogenic comparator, or to a precisely matching predicted splice event; it does not provide a PS1 route for a synonymous variant without such a comparator.
Evidence considered
The case normalization identifies NM_000059.4:c.1167G>A as synonymous, encoding NP_000050.3:p.(Pro389=)/p.(P389=).
ENIGMA BRCA2 v1.2 defines PS1 for the same missense substitution as a previously classified pathogenic variant, or for the same predicted splice event; neither pathway is established here.
SpliceAI max delta is 0.001, below the VCEP no-significant-splicing threshold of 0.1.
The governing VCEP full-text files were searched under c.1167G>A, p.Pro389=, p.P389=, and residue 389; no exact entry for this variant was found.
Still missing
No exact c.1167G>A, p.Pro389=, or p.P389= entry was found in Specifications_V1.2_2024-11-18.docx.txt.
No exact c.1167G>A, p.Pro389=, or p.P389= entry was found in Appendices_V1.2_2024-11-18.docx.txt.
No exact c.1167G>A, p.Pro389=, or p.P389= entry was found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt.
PS2VCEPNot applicable: ENIGMA explicitly prohibits PS2 for BRCA1/2 because de novo predictive capacity is uncalibrated.
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Reasoning
The ENIGMA BRCA1/2 VCEP Specification v1.2 explicitly states that PS2 is not to be used for BRCA1/2-related cancers because these cancers occur relatively commonly and the predictive capacity of de novo occurrences has not been calibrated.
VCEP rule
PS2: Do not use for BRCA1/2-related cancers; no information is available to calibrate the predictive capacity of de novo occurrences.
Evidence considered
ENIGMA BRCA1/2 Specification v1.2, Table 1: PS2 is listed as "Do not use" because BRCA1/2-related cancers are relatively common and de novo occurrences lack calibration.
The case evidence identifies the variant as NM_000059.4:c.1167G>A, but variant-level de novo evidence cannot override the governing VCEP prohibition.
PM1VCEPNot applicable: ENIGMA marks PM1 do not use, and residue 389 lies outside the approved BRCA2 domains at aa 10-40 and 2481-3186.
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Reasoning
The authoritative vcep_materials.json domain_tables key is present but empty, so the governing VCEP domain definitions were checked directly. ENIGMA BRCA2 v1.2 explicitly marks PM1 as do not use and evaluates domain-related evidence through BP1, BP4, and PP3. Its approved BRCA2 clinically important domains are PALB2 binding aa 10-40 and DNA binding aa 2481-3186; residue 389 is outside both. The synonymous consequence also does not meet the VCEP PM1 missense-domain use pathway.
VCEP rule
ENIGMA BRCA2 v1.2: PM1 is not used; domain location is evaluated through BP1, BP4, and PP3. BRCA2 approved domains are aa 10-40 and aa 2481-3186.
Evidence considered
vcep_materials.json has an empty domain_tables object, so the governing VCEP domain table was checked directly.
ENIGMA BRCA2 v1.2 states that PM1 is not used and that domain-related evidence is considered through BP1, BP4, and PP3.
The governing BRCA2 domains are PALB2 binding aa 10-40 and DNA binding aa 2481-3186; residue 389 is outside every listed domain.
PM4VCEPNot applicable: p.Pro389= changes protein sequence length by 0 amino acids, and ENIGMA explicitly excludes PM4.
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Reasoning
NM_000059.4:c.1167G>A is synonymous and produces p.(Pro389=), so it causes no protein length change, in-frame insertion/deletion, or stop-loss consequence. The governing ENIGMA BRCA1/2 Version 1.2 specification explicitly marks PM4 as not applicable and states that protein-length-change evidence is not used under this VCEP framework. No exact c.1167G>A, p.Pro389=, or p.P389= entry 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
ENIGMA BRCA1/2 V1.2 marks PM4 as not applicable; the synonymous p.Pro389= consequence also produces no protein length change.
Evidence considered
Variant normalization confirms a synonymous substitution with p.(Pro389=)/p.(P389=), indicating zero amino-acid residues inserted or deleted and no stop-loss event.
ENIGMA BRCA1/2 Version 1.2 Table 1 states that PM4 for protein length changes due to in-frame insertions/deletions or stop-loss variants is not applicable and is not used.
The governing VCEP files were searched for c.1167G>A, p.Pro389=, and p.P389=; no exact variant entry was found.
Still missing
No exact c.1167G>A, p.Pro389=, or p.P389= entry was found in Specifications_V1.2_2024-11-18.docx.txt.
No exact c.1167G>A, p.Pro389=, or p.P389= entry was found in Appendices_V1.2_2024-11-18.docx.txt.
No exact c.1167G>A, p.Pro389=, or p.P389= entry was found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt.
No exact c.1167G>A, p.Pro389=, or p.P389= entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
PM5N/ANot applicable: ENIGMA repurposes PM5 exclusively for genomic PTC variants, whereas this variant is synonymous and not a protein-termination codon.
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Reasoning
The classic PM5 rule concerns a novel missense change at a residue where a different pathogenic missense change has been observed. ENIGMA BRCA2 v1.2 explicitly says classic PM5 is not used and repurposes PM5 only as PM5 (PTC) for genomic protein-termination-codon variants. This variant is synonymous, not a PTC, so alternate same-residue missense observations such as BRCA2 p.Pro389Gln and p.Pro389Leu cannot activate the governing PM5 rule.
Rule
ENIGMA BRCA2 v1.2: classic PM5 is not used; PM5 is repurposed as PM5 (PTC) only for genomic PTC variants, with exon-specific Table 4 weights.
Evidence considered
ENIGMA BRCA2 v1.2 marks classic missense PM5 as do not use and repurposes PM5 as PM5 (PTC) for genomic protein-termination-codon variants only.
The case variant is synonymous, NM_000059.4:c.1167G>A, p.(Pro389=), and is not a PTC.
The VCEP full-text search identified alternate same-residue missense records p.Pro389Gln and p.Pro389Leu, but those do not satisfy the governing PM5 (PTC) rule.
Still missing
No exact c.1167G>A, p.Pro389=, or p.P389= entry was found in Specifications_V1.2_2024-11-18.docx.txt.
No exact c.1167G>A, p.Pro389=, or p.P389= entry was found in Appendices_V1.2_2024-11-18.docx.txt.
No exact c.1167G>A, p.Pro389=, or p.P389= entry was found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt.
PM6VCEPNot applicable: ENIGMA explicitly prohibits PM6 for BRCA1/2 because de novo predictive capacity is uncalibrated.
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Reasoning
The ENIGMA BRCA1/2 VCEP Specification v1.2 explicitly states that PM6 is not to be used for BRCA1/2-related cancers because these cancers occur relatively commonly and the predictive capacity of de novo occurrences has not been calibrated.
VCEP rule
PM6: Do not use for BRCA1/2-related cancers; no information is available to calibrate the predictive capacity of de novo occurrences.
Evidence considered
ENIGMA BRCA1/2 Specification v1.2, Table 1: PM6 is listed as "Do not use" for BRCA1/2-related cancers for the same calibration reason as PS2.
The absence or presence of unconfirmed-parentage de novo observations cannot be converted into PM6 under the governing VCEP rule.
PP2VCEPNot applicable: ENIGMA marks PP2 do not use for BRCA2, and the queried variant is synonymous rather than missense.
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Reasoning
ENIGMA BRCA2 v1.2 explicitly marks PP2 as do not use because missense variants are not a common mechanism of pathogenicity for BRCA1 and BRCA2. The queried variant is additionally synonymous rather than missense, so PP2 cannot be applied.
VCEP rule
ENIGMA BRCA2 v1.2: PP2 is not applicable because missense variants are not a common mechanism of pathogenicity for BRCA1/2.
Evidence considered
ENIGMA BRCA2 v1.2 states that PP2 is not used because missense variants are not a common pathogenic mechanism in BRCA1 and BRCA2.
The case normalization identifies c.1167G>A as a synonymous variant, not a missense variant.
BP2VCEPNot applicable: ENIGMA BRCA2 specification states BP2 is not used and is applied only in the context of BS2.
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Reasoning
The ENIGMA BRCA1/2 VCEP specification explicitly states that BP2 is not used and is applied only in the context of BS2. No BP2 evidence may therefore be assigned for this BRCA2 variant under the governing framework.
VCEP rule
ENIGMA BRCA2 VCEP BP2: do not use; applied only in the context of BS2.
Evidence considered
ENIGMA BRCA1/2 Specification V1.2 Table 1 lists BP2 as 'Do not use' and states that it is applied only in the context of BS2.
Still missing
No c.1167G>A, p.Pro389=, or p.P389= entry was found when Specifications_V1.2_2024-11-18.docx.txt was searched; this is a VCEP-file search gap, not evidence that allelic observations are absent.
BP3VCEPNot applicable: c.1167G>A is a synonymous substitution, not an in-frame insertion/deletion in a repetitive region.
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Reasoning
NM_000059.4:c.1167G>A is a synonymous single-nucleotide substitution, not an in-frame deletion or insertion in a repetitive region without known function. The governing ENIGMA BRCA1/2 Version 1.2 specification explicitly marks BP3 as not applicable and states that such evidence is captured through bioinformatic and domain analysis instead. No exact c.1167G>A, p.Pro389=, or p.P389= entry 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
ENIGMA BRCA1/2 V1.2 marks BP3 as not applicable and restricts it to in-frame insertions/deletions in repetitive regions without known function.
Evidence considered
Variant normalization confirms a synonymous single-nucleotide substitution, not an in-frame insertion or deletion.
ENIGMA BRCA1/2 Version 1.2 Table 1 defines BP3 for in-frame deletions/insertions in repetitive regions without known function and explicitly marks the criterion not applicable.
The governing VCEP files were searched for c.1167G>A, p.Pro389=, and p.P389=; no exact variant entry was found.
Still missing
No exact c.1167G>A, p.Pro389=, or p.P389= entry was found in Specifications_V1.2_2024-11-18.docx.txt.
No exact c.1167G>A, p.Pro389=, or p.P389= entry was found in Appendices_V1.2_2024-11-18.docx.txt.
No exact c.1167G>A, p.Pro389=, or p.P389= entry was found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt.
No exact c.1167G>A, p.Pro389=, or p.P389= entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
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…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in BRCA2—Select a row to find it on the plot; use the link to open its page.
Protein
Location
Classification
Link
gnomAD v4.1Allele count data not recorded
gnomAD v2.1Allele count data not recorded
gnomAD-Canada v1.0Allele count data not recorded
Statements
gnomAD v4.1
The gnomAD v4.1 query FAILED for this variant, so its frequency in v4.1 is UNKNOWN. This is missing data, NOT evidence of absence or rarity, and must not support PM2 or any frequency-based criterion.
gnomAD v2.1
The gnomAD v2.1 query FAILED for this variant, so its frequency in v2.1 is UNKNOWN. This is missing data, NOT evidence of absence or rarity, and must not support PM2 or any frequency-based criterion.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
SpliceAI and Pangolin
SpliceAI acceptor lossat +390 bp
0.000
SpliceAI acceptor gainat +331 bp
0.000
SpliceAI donor lossat +37 bp
0.000
SpliceAI donor gainat -201 bp
0.001
Pangolin splice lossmagnitude shown
-0.001
Pangolin splice gain
0.008
Other predictors
REVEL
Not available
BayesDel
Not available
How the predictions were used
PP3Not met: SpliceAI maximum delta 0.001 is below the ENIGMA PP3 threshold of 0.2 for silent variants.
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Reasoning
The variant is synonymous (NM_000059.4:c.1167G>A; NP_000050.3:p.(Pro389=)), so the applicable computational path is SpliceAI rather than REVEL. SpliceAI is available and its maximum delta score is 0.001, below the ENIGMA BRCA2 PP3 splice-prediction threshold of 0.2; therefore PP3 is not met. The governing ENIGMA specification states that PP3 may be applied to silent variants when SpliceAI is at least 0.2. No exact variant entry was found when searching Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, or PMID_22505045_Houdayer_2012_HumMutat.pdf.txt for c.1167G>A, p.Pro389=, and p.P389=.
Rule
ENIGMA BRCA2 v1.2 PP3: predicted splicing with SpliceAI ≥0.2 for silent variants.
Evidence considered
The case normalization identifies NM_000059.4:c.1167G>A as synonymous, encoding NP_000050.3:p.(Pro389=); REVEL is therefore not the applicable path.
SpliceAI reports DS_AG 0.0, DS_AL 0.0, DS_DG 0.001, and DS_DL 0.0, with maximum delta 0.001.
ENIGMA BRCA2 Specifications v1.2 states: apply PP3 for predicted splicing (SpliceAI ≥0.2) for silent variants.
The exact-variant searches found no entry in the three governing full-text files.
Still missing
No exact c.1167G>A, p.Pro389=, or p.P389= entry was found in Specifications_V1.2_2024-11-18.docx.txt.
No exact c.1167G>A, p.Pro389=, or p.P389= entry was found in Appendices_V1.2_2024-11-18.docx.txt.
No exact c.1167G>A, p.Pro389=, or p.P389= entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
BP4Not met: SpliceAI maximum delta 0.001 is below 0.1, but ENIGMA BP4 requires a silent variant inside a clinically important BRCA2 domain.
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Reasoning
The variant is synonymous (NM_000059.4:c.1167G>A; NP_000050.3:p.(Pro389=)), so the applicable computational path is SpliceAI rather than REVEL. SpliceAI maximum delta is 0.001, numerically below the ENIGMA no-splicing threshold of 0.1, but ENIGMA v1.2 restricts computational BP4 for silent variants to those inside a potentially clinically important functional domain. Pro389 is outside the BRCA2 PALB2-binding domain (aa 10-40) and DNA-binding domain (aa 2481-3186), so the governing BP4 rule is not satisfied. No exact variant entry was found when searching Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, or PMID_22505045_Houdayer_2012_HumMutat.pdf.txt for c.1167G>A, p.Pro389=, and p.P389=.
Rule
ENIGMA BRCA2 v1.2 BP4: for silent variants, SpliceAI ≤0.1 and location inside a potentially clinically important functional domain.
Evidence considered
The case normalization identifies NM_000059.4:c.1167G>A as synonymous at protein position Pro389; REVEL is not applicable.
SpliceAI reports maximum delta 0.001, which is ≤0.1, but this numerical result does not override the VCEP's domain requirement.
ENIGMA BRCA2 Specifications v1.2 defines the relevant domains as PALB2 binding aa 10-40 and DNA binding aa 2481-3186; Pro389 lies outside both.
The exact-variant searches found no entry in the three governing full-text files.
Still missing
No exact c.1167G>A, p.Pro389=, or p.P389= entry was found in Specifications_V1.2_2024-11-18.docx.txt.
No exact c.1167G>A, p.Pro389=, or p.P389= entry was found in Appendices_V1.2_2024-11-18.docx.txt.
No exact c.1167G>A, p.Pro389=, or p.P389= entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
BP7Not met: Pro389 lies outside ENIGMA's qualifying domains, and no mRNA-only assay supports the alternative BP7_Strong route.
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Reasoning
The variant is synonymous, so BP7 is within criterion scope. However, ENIGMA v1.2 computational BP7 requires a silent variant inside a potentially clinically important functional domain and BP4 met; Pro389 is outside the BRCA2 PALB2-binding domain (aa 10-40) and DNA-binding domain (aa 2481-3186), so that supporting BP7 route is unavailable. The alternative BP7_Strong (RNA) route requires a well-established mRNA-only functional assay, and no such assay is present in the available evidence. No exact variant entry was found when searching Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, or PMID_22505045_Houdayer_2012_HumMutat.pdf.txt for c.1167G>A, p.Pro389=, and p.P389=.
Rule
ENIGMA BRCA2 v1.2 BP7: silent variant inside a potentially clinically important functional domain if BP4 is met; BP7_Strong (RNA) requires an mRNA-only functional assay.
Evidence considered
The case normalization identifies NM_000059.4:c.1167G>A as a synonymous p.(Pro389=) variant.
ENIGMA BRCA2 Specifications v1.2 requires computational BP7 for silent variants to be inside a potentially clinically important functional domain and requires BP4 to be met.
Pro389 is outside the ENIGMA BRCA2 PALB2-binding domain aa 10-40 and DNA-binding domain aa 2481-3186.
No well-established mRNA-only functional assay for this variant is present in the available evidence.
The exact-variant searches found no entry in the three governing full-text files.
Still missing
No exact c.1167G>A, p.Pro389=, or p.P389= entry was found in Specifications_V1.2_2024-11-18.docx.txt.
No exact c.1167G>A, p.Pro389=, or p.P389= entry was found in Appendices_V1.2_2024-11-18.docx.txt.
No exact c.1167G>A, p.Pro389=, or p.P389= entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
9 paper records listed. 1 cited in the classification.
Cited in the classification
Mutation analysis of BRCA1 and BRCA2 from 793 Korean patients with sporadic breast cancer.
Han SH et al. · 2006 Dec
The paper reports a BRCA2 exon 10 synonymous variant written as 1395G>A, p.P389P, corresponding to the queried synonymous amino-acid change notation, in 6 of 793 Korean patients with sporadic breast cancer and none of 167 normal controls; it was classified as a polymorphism and no variant-specific functional or segregation assay was reported.
Location Table 2, Sequence alterations detected in BRCA2, Polymorphisms
Context 793 Korean patients with sporadic breast cancer and 167 normal controls; BRCA1/BRCA2 coding exons and exon-intron boundaries were screened by DHPLC and sequencing.
Other recorded publications
Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study.
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.
Identification of BRCA1 and BRCA2 mutations from Korean breast cancer patients using denaturing HPLC.
Kim BY et al. · 2006
The paper reports a BRCA2 exon 10 synonymous variant written as 1395G>A, p.P389P, as a novel polymorphism observed in 3 of 1020 Korean breast cancer patients and 3 of 167 unaffected controls; no variant-specific functional, segregation, or disease-specific interpretation was reported.
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
The gnomAD v4.1 query FAILED for this variant, so its frequency in v4.1 is UNKNOWN. This is missing data, NOT evidence of absence or rarity, and must not support PM2 or any frequency-based criterion.
gnomAD v2.1
The gnomAD v2.1 query FAILED for this variant, so its frequency in v2.1 is UNKNOWN. This is missing data, NOT evidence of absence or rarity, and must not support PM2 or any frequency-based criterion.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Likely benign (9 clinical laboratories) and as Benign (4 clinical laboratories) and as Uncertain significance (1 clinical laboratory) and as Likely benign by Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) (expert panel). (ClinVarID = 184355)
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.
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