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: maximum non-cancer gnomAD FAF 0.00007569 falls between the ENIGMA BS1 Supporting limits of greater than 0.00002 and at most 0.0001.
BP1Strong
BP1 · strong
Met at strong: synonymous residue Ser2148 is outside approved domains, and SpliceAI maximum delta 0.01 meets the <=0.1 threshold.
BP6Supporting
BP6 · supporting
Met, Supporting: ClinVar expert panel classifies the exact variant as Likely benign, satisfying the requested BP6 expert-panel rule.
Recorded classification: Likely benign
Likely Benign: BS1 supporting (+1) is outweighed by BP1 strong (-4) and BP6 supporting (-1), yielding ENIGMA's -4 Likely Benign range.
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
30 / 1,592,250 alleles
gnomAD v4.1: 30 / 1,592,250 alleles. Recorded AF 1.88413e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 2.605e-05; MAF= 0.00261%, 6/230326 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000193513; MAF= 0.01935%, 5/25838 alleles, homozygotes = 0); grpmax FAF= 7.548e-05.
ACMG/AMP criteria under ClinGen BRCA2 VCEP v1.2, with the data and sources behind each one.
28 criteria with recorded statuses: 3 met · 4 not met · 9 not assessed · 12 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
For the requested consequence/LOF criteria, the variant is a synonymous NM_000059.4 coding substitution with p.(Ser2148=), SpliceAI max delta 0.01, and no protein-length change; the governing ENIGMA BRCA2 VCEP rules therefore make PVS1, PM4, and BP3 not applicable.
The three named VCEP-governed files and the Houdayer paper were searched under all three requested variant notations; no variant-specific pre-assigned entry was found in those files.
For the requested codon, residue, and domain criteria, the only applicable criterion is BP1_Strong: the variant is synonymous, lies outside the approved BRCA2 functional domains, and has SpliceAI maximum delta 0.01.
PS1, PM1, PM5, and PP2 are not applicable under the governing ENIGMA BRCA2 specification and the variant's synonymous consequence.
For this synonymous BRCA2 variant, no exact-variant PS4 case-control result or PP4/BP5 multifactorial LR was available from the governing VCEP sources.
The exact ClinVar expert-panel classification is Likely benign, supporting BP6 and not PP5 under the requested expert-panel-only rule.
For NM_000059.4:c.6444T>C (p.(Ser2148=)), the applicable splice predictor is SpliceAI, which reports max delta 0.01.
ENIGMA v1.2 sets the PP3 splice-impact threshold at SpliceAI >=0.2, so PP3 is not met.
The ENIGMA silent-variant BP4 and BP7 pathways require location inside a specified BRCA2 functional domain; Ser2148 is outside both specified domains, so BP4 and BP7 are not applicable.
No criteria match.
Met · 3
BS1SupportingMet at supporting: maximum non-cancer gnomAD FAF 0.00007569 falls between the ENIGMA BS1 Supporting limits of greater than 0.00002 and at most 0.0001.
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Reasoning
The ENIGMA BRCA1/2 VCEP v1.2 assigns BS1 Supporting when maximum non-founder gnomAD filter allele frequency is greater than 0.00002 and less than or equal to 0.0001, and BS1 Strong only above 0.0001. The variant's maximum reported non-cancer gnomAD v2.1 exome FAF is 0.00007569, placing it in the VCEP Supporting interval; it is absent from gnomAD v3.1 non-cancer. Therefore BS1 is met at Supporting strength, not Strong. No variant-specific row for c.6444T>C, p.Ser2148=, or p.S2148= 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; the governing VCEP population rule was found in the specification and appendix texts.
Rule
ENIGMA BS1 Supporting: maximum non-founder gnomAD FAF > 0.00002 and <= 0.0001; BS1 Strong requires >0.0001; do not apply if read depth <20.
Evidence considered
ENIGMA v1.2 specifies BS1 Strong above 0.0001 and BS1 Supporting above 0.00002 through 0.0001, using maximum non-founder gnomAD FAF and separate exome/genome assessment.
The non-cancer gnomAD v2.1 exome result is 6/215906 alleles, AF 2.778987151816068e-05, with maximum population FAF 7.568999999999996e-05 and zero homozygotes.
The variant is absent from gnomAD v3.1 non-cancer, so the observed v2.1 non-cancer FAF remains the applicable maximum reported FAF.
Still missing
No variant-specific row for c.6444T>C, p.Ser2148=, or p.S2148= was found in Specifications_V1.2_2024-11-18.docx.txt.
No variant-specific row for c.6444T>C, p.Ser2148=, or p.S2148= was found in Appendices_V1.2_2024-11-18.docx.txt.
No variant-specific row for c.6444T>C, p.Ser2148=, or p.S2148= was found in HUMU-40-1557-s001.xlsx.txt.
BP1StrongMet at strong: synonymous residue Ser2148 is outside approved domains, and SpliceAI maximum delta 0.01 meets the <=0.1 threshold.
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Reasoning
ENIGMA BRCA2 BP1_Strong applies to silent substitutions outside a potentially clinically important functional domain when no splicing is predicted. The variant is synonymous at residue Ser2148, outside the approved BRCA2 PALB2-binding domain aa 10-40 and DNA-binding domain aa 2481-3186, and SpliceAI reports a maximum delta of 0.01, meeting the <=0.1 no-splicing threshold.
Rule
Apply BP1_Strong for a silent substitution outside an approved BRCA2 functional domain and with no predicted splicing impact (SpliceAI <=0.1).
Evidence considered
ENIGMA specification v1.2 assigns BP1_Strong to silent substitutions outside a potentially clinically important functional domain with SpliceAI <=0.1.
The approved BRCA2 domains are PALB2 binding aa 10-40 and DNA binding aa 2481-3186; residue Ser2148 is outside both domains.
SpliceAI reports DS_AG 0.00, DS_AL 0.01, DS_DG 0.00, and DS_DL 0.00; maximum delta score 0.01 is below the <=0.1 threshold.
Still missing
No entry for c.6444T>C, p.Ser2148=, or p.S2148= was found in Specifications_V1.2_2024-11-18.docx.txt.
No entry for c.6444T>C, p.Ser2148=, or p.S2148= was found in Appendices_V1.2_2024-11-18.docx.txt.
No entry for c.6444T>C, p.Ser2148=, or p.S2148= was found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt.
BP6SupportingMet, Supporting: ClinVar expert panel classifies the exact variant as Likely benign, satisfying the requested BP6 expert-panel rule.
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Reasoning
Expert panel Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) classified as Likely benign.
Rule
Apply BP6 at Supporting strength only for an exact-variant ClinVar expert-panel classification of Benign or Likely benign; ordinary laboratory submissions and aggregate labels do not trigger BP6.
Evidence considered
ClinVar variation 415692 exactly matches NM_000059.4(BRCA2):c.6444T>C (p.Ser2148=) and reports Likely benign with expert-panel review status.
The requested BP6 rule allows Supporting BP6 only for an exact-variant ClinVar expert-panel classification of Benign or Likely benign; this condition is satisfied.
Six additional laboratory submissions and aggregate ClinVar labels were not used as the trigger.
PM2Not met: the variant is present at 6/215906 alleles in non-cancer gnomAD v2.1 exomes, so ENIGMA's required absence from both datasets is not satisfied.
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Reasoning
The ENIGMA BRCA1/2 VCEP permits PM2 Supporting only when the variant is absent from controls in both gnomAD v2.1 non-cancer exomes and gnomAD v3.1 non-cancer genomes, with average local read depth at least 25. This variant is present in gnomAD v2.1 non-cancer exomes at 6/215906 alleles (AF 2.778987151816068e-05), although it is absent from gnomAD v3.1 non-cancer; because the required two-dataset absence condition is not satisfied, PM2 is not met. No variant-specific row for c.6444T>C, p.Ser2148=, or p.S2148= 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; the governing VCEP population rule was found in the specification and appendix texts.
Rule
ENIGMA PM2 Supporting: absent from gnomAD v2.1 non-cancer exome-only controls and gnomAD v3.1 non-cancer controls, with average local read depth >=25; a single observation is not informative.
Evidence considered
ENIGMA v1.2 specifies PM2 Supporting for absence from controls in both gnomAD v2.1 non-cancer exome-only data and gnomAD v3.1 non-cancer genomes, with local average read depth at least 25.
The variant is present in non-cancer gnomAD v2.1 exomes at 6/215906 alleles, AF 2.778987151816068e-05, with zero homozygotes.
The variant is absent from gnomAD v3.1 non-cancer, but absence in only one of the two required datasets does not meet PM2.
Still missing
No variant-specific row for c.6444T>C, p.Ser2148=, or p.S2148= was found in Specifications_V1.2_2024-11-18.docx.txt.
No variant-specific row for c.6444T>C, p.Ser2148=, or p.S2148= was found in Appendices_V1.2_2024-11-18.docx.txt.
No variant-specific row for c.6444T>C, p.Ser2148=, or p.S2148= was found in HUMU-40-1557-s001.xlsx.txt.
PP3Not met: SpliceAI max delta 0.01 is below the ENIGMA PP3 threshold of 0.2 for predicted splicing in silent variants.
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Reasoning
The variant is synonymous, so the applicable computational path is SpliceAI rather than REVEL. ENIGMA BRCA1/2 Specification v1.2 applies PP3 to predicted splicing for silent variants at SpliceAI max delta >=0.2; the case SpliceAI result is max delta 0.01 (DS_AG 0.00, DS_AL 0.01, DS_DG 0.00, DS_DL 0.00), below the governing threshold. No variant-specific PP3 pre-assignment was found in Specifications_V1.2_2024-11-18.docx, Appendices_V1.2_2024-11-18.docx, or PMID_22505045_Houdayer_2012_HumMutat.pdf.
Rule
ENIGMA v1.2 PP3: silent variant with predicted splicing requires SpliceAI max delta >=0.2.
Evidence considered
ENIGMA BRCA1/2 Specification v1.2 states that PP3 applies to predicted splicing for silent variants at SpliceAI >=0.2.
SpliceAI reports DS_AG 0.00, DS_AL 0.01, DS_DG 0.00, and DS_DL 0.00; the maximum delta is 0.01.
The variant is NM_000059.4:c.6444T>C, p.(Ser2148=), a synonymous substitution, so REVEL is not the applicable predictor path.
Still missing
No variant-specific PP3 entry was found in Specifications_V1.2_2024-11-18.docx.
No variant-specific PP3 entry was found in Appendices_V1.2_2024-11-18.docx.
No variant-specific PP3 entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.
PP5Not met: the exact ClinVar expert-panel classification is Likely benign, whereas PP5 requires Pathogenic or Likely pathogenic expert-panel classification.
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Reasoning
The exact variant NM_000059.4(BRCA2):c.6444T>C (p.Ser2148=) has a ClinVar expert-panel classification of Likely benign, not Pathogenic or Likely pathogenic. Under the requested exact-variant expert-panel-only rule, this benign-direction classification does not support PP5. Ordinary laboratory submissions and aggregate labels were not used to trigger the criterion. The ENIGMA specification separately labels PP5 not applicable for this VCEP, but the requested rule permits only the specified expert-panel direction and that direction is benign.
Rule
Apply PP5 only for an exact-variant ClinVar expert-panel classification of Pathogenic or Likely pathogenic; ordinary laboratory submissions and aggregate labels do not trigger PP5.
Evidence considered
ClinVar variation 415692 identifies NM_000059.4(BRCA2):c.6444T>C (p.Ser2148=) and reports Likely benign with review status reviewed by expert panel.
The exact expert-panel result is benign-direction; no Pathogenic or Likely pathogenic expert-panel classification exists in the supplied ClinVar evidence.
The ENIGMA specification text says PP5 is not applicable for this VCEP; this was recorded but does not convert the benign expert-panel result into pathogenic evidence.
BA1Not met: maximum non-cancer gnomAD FAF is 0.00007569, below the ENIGMA BA1 threshold of greater than 0.001.
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Reasoning
The ENIGMA BRCA1/2 VCEP v1.2 requires maximum non-founder gnomAD filter allele frequency above 0.001 for BA1, using gnomAD v2.1 non-cancer exomes and/or gnomAD v3.1 non-cancer genomes. The variant's maximum reported non-cancer gnomAD v2.1 exome FAF is 0.00007569 (6/215906 alleles; South Asian maximum), and it is absent from gnomAD v3.1 non-cancer, so the BA1 threshold is not reached. The all-comers gnomAD v4.1 grpmax FAF is also only 0.00007973. No variant-specific row for c.6444T>C, p.Ser2148=, or p.S2148= 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; the governing VCEP population rule itself was found in the specification and appendix texts.
Rule
ENIGMA BA1: maximum non-founder gnomAD FAF > 0.001 in gnomAD v2.1 non-cancer exome-only and/or gnomAD v3.1 non-cancer genomes; do not apply if read depth <20.
Evidence considered
ENIGMA v1.2 specifies BA1 when maximum non-founder gnomAD filter allele frequency is greater than 0.001, with read depth at least 20.
The non-cancer gnomAD v2.1 exome result is 6/215906 alleles, AF 2.778987151816068e-05, with maximum population FAF 7.568999999999996e-05 and zero homozygotes.
The variant is absent from gnomAD v3.1 non-cancer; the all-comers gnomAD v4.1 grpmax FAF is 7.972999999999998e-05, also below 0.001.
Still missing
No variant-specific row for c.6444T>C, p.Ser2148=, or p.S2148= was found in Specifications_V1.2_2024-11-18.docx.txt.
No variant-specific row for c.6444T>C, p.Ser2148=, or p.S2148= was found in Appendices_V1.2_2024-11-18.docx.txt.
No variant-specific row for c.6444T>C, p.Ser2148=, or p.S2148= was found in HUMU-40-1557-s001.xlsx.txt.
PS3Not assessed: no variant-specific damaging functional assay or governing ENIGMA Table 9 entry was found for c.6444T>C (p.Ser2148=).
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Reasoning
The ENIGMA BRCA1/2 specification requires PS3 functional evidence to come from well-established assays showing a damaging effect, with protein-only or combined mRNA/protein assays eligible and calibrated strength assigned through Table 9. Searches of Specifications_Table9_V1.2_2024-11-18.xlsx.txt, Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, and HUMU-40-1557-s001.xlsx.txt found no entry for c.6444T>C, p.Ser2148=, or p.S2148=. The case evidence bundle contains no variant-specific functional assay result or relevant functional publication, so PS3 cannot be assigned.
Rule
Well-established in vitro or in vivo functional studies supportive of a damaging effect; apply PS3 for assays measuring protein function only or mRNA and protein combined, using calibrated VCEP Table 9 recommendations.
Evidence considered
ENIGMA BRCA1/2 v1.2 specifies PS3 for well-established in vitro or in vivo functional studies showing a damaging effect; protein-only or combined mRNA/protein assays are eligible, and Table 9 provides calibrated recommendations.
The governing VCEP full-text files were searched under all three requested variant notations: c.6444T>C, p.Ser2148=, and p.S2148=; no matching functional-assay row was found.
The case bundle reports no variant-specific functional assay finding for BRCA2 c.6444T>C (p.Ser2148=), and the extracted publications are not functional studies of this variant.
Still missing
No entry for c.6444T>C, p.Ser2148=, or p.S2148= in Specifications_Table9_V1.2_2024-11-18.xlsx.txt.
No entry for c.6444T>C, p.Ser2148=, or p.S2148= in Specifications_V1.2_2024-11-18.docx.txt.
No entry for c.6444T>C, p.Ser2148=, or p.S2148= in Appendices_V1.2_2024-11-18.docx.txt.
No entry for c.6444T>C, p.Ser2148=, or p.S2148= in HUMU-40-1557-s001.xlsx.txt.
No variant-specific damaging functional assay result is present in the case evidence bundle or its fetched paper extracts.
PS4Not assessed: no exact-variant case-control p-value, OR, and confidence interval were available to compare with the ENIGMA PS4 thresholds.
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Reasoning
The ENIGMA BRCA2 specification defines PS4 Strong for a case-control study with p-value <=0.05, odds ratio (OR) >=4, and a lower confidence interval that excludes 2.0. No exact-variant case-control result for NM_000059.4:c.6444T>C / p.Ser2148= / p.S2148= was found. HUMU-40-1557-s001.xlsx was searched and its available target-like entry is c.6443C>A / p.Ser2148Tyr, a different variant; it cannot be used for this synonymous variant. SupplementaryTables_V1.2.xlsx was searched as declared but its full text is unavailable, which is a conversion gap rather than evidence of absence. The Specifications_V1.2_2024-11-18.docx text was searched and supplied the PS4 rule but no exact-variant result. Therefore PS4 cannot be assessed.
Rule
Case-control studies; p-value <=0.05 and OR >=4 (lower confidence interval excludes 2.0).
Evidence considered
The ENIGMA specification states: "Case-control studies; p-value <=0.05 and OR >=4 (lower confidence interval excludes 2.0)."
HUMU-40-1557-s001.xlsx was searched under all three requested notations; the available same-codon row is c.6443C>A / p.(Ser2148Tyr), not c.6444T>C / p.(Ser2148=).
SupplementaryTables_V1.2.xlsx is declared as the ST7 posterior-probability source for PS4, but its full text was unavailable after conversion and no assumption was made about its contents.
Still missing
No exact-variant entry found in HUMU-40-1557-s001.xlsx after searching c.6444T>C, p.Ser2148=, and p.S2148=.
No exact-variant entry found in Specifications_V1.2_2024-11-18.docx.txt after searching c.6444T>C, p.Ser2148=, and p.S2148=.
SupplementaryTables_V1.2.xlsx was declared for PS4 and searched, but its full text is unavailable because conversion failed; this is a data-conversion gap.
No exact-variant case-control p-value, odds ratio, or confidence interval was available.
PM3Not assessed: no documented Fanconi anemia phenotype, chromosome-breakage result, or phased pathogenic/likely pathogenic BRCA2 variant supports the VCEP PM3 requirement.
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Reasoning
The ENIGMA BRCA2 VCEP specification restricts PM3 to individuals with a phenotype consistent with BRCA1/2-related Fanconi anemia and a co-occurring pathogenic or likely pathogenic variant in the same gene, with strength assigned from PM3 points (Supporting = 1, Moderate = 2, Strong = 4 or more). The available case evidence provides no affected-proband Fanconi anemia phenotype, chromosome-breakage result, phase information, or documented pathogenic/likely pathogenic BRCA2 variant in trans or cis. The governing Specifications_V1.2_2024-11-18.docx.txt was searched for c.6444T>C, p.Ser2148=, and p.S2148=; no variant-specific PM3 entry was found. Therefore PM3 cannot be assessed from the available allelic evidence.
Rule
Apply 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; PM3_Supporting = 1 point, PM3 = 2 points, PM3_Strong = 4 or more points.
Evidence considered
ENIGMA BRCA2 VCEP PM3 rule: apply only for a patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi anemia and a co-occurring variant in the same gene; PM3 strength is based on points, with Supporting = 1, Moderate = 2, and Strong = 4 or more.
The case evidence contains no documented Fanconi anemia phenotype, chromosome-breakage result, phased pathogenic/likely pathogenic BRCA2 partner, or affected-proband observation establishing PM3 points.
Specifications_V1.2_2024-11-18.docx.txt was searched for c.6444T>C, p.Ser2148=, and p.S2148=; no variant-specific PM3 entry was found.
Still missing
No affected-proband Fanconi anemia phenotype or qualifying chromosome-breakage result is documented.
No pathogenic or likely pathogenic BRCA2 co-occurring variant with documented phase is provided.
No variant-specific entry for c.6444T>C, p.Ser2148=, or p.S2148= was found in Specifications_V1.2_2024-11-18.docx.txt after searching all three notations.
PP1Not assessed: no family-level segregation data or quantitative LR was available, so ENIGMA PP1 thresholds of 2.08, 4.3, 18.7, and 350 cannot be applied.
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Reasoning
No variant-specific affected-family segregation observations, parental testing results, meioses, pedigree data, or quantitative co-segregation likelihood ratio were identified for NM_000059.4:c.6444T>C (NP_000050.3:p.(Ser2148=)). ENIGMA requires quantitative co-segregation analysis and assigns PP1 Supporting at LR ≥2.08, Moderate at LR ≥4.3, Strong at LR ≥18.7, and Very Strong at LR ≥350; none can be evaluated without family-level data. The case literature extracts contain no variant-specific segregation paper finding. The searched HUMU-40-1557-s001 converted text had no entry for c.6444T>C, p.Ser2148=, or p.S2148=; SupplementaryTables_V1.2.xlsx full text is unavailable and remains a lookup gap.
Rule
Apply PP1 only from quantitative co-segregation analysis under ENIGMA V1.2 thresholds.
Evidence considered
The case evidence bundle and directly reviewed case evidence contain no variant-specific family segregation, parental testing, meiosis, pedigree, or co-segregation LR result for NM_000059.4:c.6444T>C.
ENIGMA V1.2 PP1 requires quantitative co-segregation analysis: Supporting LR ≥2.08, Moderate LR ≥4.3, Strong LR ≥18.7, and Very Strong LR ≥350.
The on-record HUMU-40-1557-s001 VCEP text was searched under c.6444T>C, p.Ser2148=, and p.S2148=; no matching variant entry was found.
Still missing
No variant-specific pedigree, affected-relative testing, parental testing, meiosis count, or quantitative co-segregation LR was found in the case evidence.
HUMU-40-1557-s001 was searched for c.6444T>C, p.Ser2148=, and p.S2148= with no entry found.
SupplementaryTables_V1.2.xlsx is declared by the BRCA2 VCEP index for PP1-adjacent clinical evidence review, but its full text was unavailable for conversion; this is a file-access gap, not evidence of absence.
PP4Not assessed: no exact-variant multifactorial likelihood ratio was available to compare with the ENIGMA PP4 threshold of >=2.08.
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Reasoning
The ENIGMA specification restricts PP4 to combined multifactorial likelihood evidence and defines Supporting as LR >=2.08, Moderate as LR >=4.3, Strong as LR >=18.7, and Very Strong as LR >=350. The gene-specific PMID_31853058_BRCA2_clinical_history_LR.xlsx source was searched for exact Gene=BRCA2 and c.6444T>C, p.Ser2148=, and p.S2148=, but no exact-variant clinical-history LR was found. The Li 2020 and Easton 2007 sources provide methodology rather than an exact-variant LR in the supplied evidence. Thus no PP4 strength can be assigned.
Rule
Use only combined multifactorial likelihood clinical data; Supporting LR >=2.08:1, Moderate LR >=4.3:1, Strong LR >=18.7:1, Very Strong LR >=350:1.
Evidence considered
The ENIGMA PP4 rules state Supporting LR >=2.08:1, Moderate LR >=4.3:1, Strong LR >=18.7:1, and Very Strong LR >=350:1.
The gene-specific clinical-history LR table was searched by exact BRCA2 gene and all requested coding/protein notations; no c.6444T>C / p.Ser2148= row was found.
The VCEP index states that the Li 2020 table is for clinical-history LR only and that Easton 2007 is methodology/context; neither can substitute for a missing exact-variant LR.
Still missing
No exact-variant entry found in PMID_31853058_BRCA2_clinical_history_LR.xlsx after searching c.6444T>C, p.Ser2148=, and p.S2148=.
PMID:31853058 and PMID:17924331 were available as methodology/context sources but did not provide an exact-variant LR in the supplied evidence.
No combined LR was available for explicit inequality evaluation.
BS2Not assessed: gnomAD reports zero homozygotes, but ENIGMA requires phenotyped clinical or research cohort observations rather than population-frequency homozygotes for BS2.
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Reasoning
The ENIGMA BRCA1/2 VCEP applies BS2 from phenotyped clinical or research cohorts showing the variant in trans with a pathogenic or likely pathogenic BRCA2 variant, or as a homozygote, in an individual without the relevant Fanconi Anemia phenotype; points are assigned using age or cancer-follow-up criteria and summed across probands. The available population data show zero homozygotes in gnomAD v2.1 non-cancer exomes, gnomAD v4.1, and the reported gnomAD datasets, but the VCEP explicitly states that homozygotes observed in gnomAD must not be used for BS2 because frequency-based evidence is handled by BA1/BS1. No qualifying phenotyped clinical or research cohort observation, phase information, age/follow-up, or Fanconi Anemia assessment was identified in the reviewed case evidence.
Rule
ENIGMA BS2: use only qualifying phenotyped clinical or research cohort observations with the Table 8 point scheme; do not use homozygotes from gnomAD frequency data.
Evidence considered
ENIGMA Table 8 assigns BS2 points from phenotyped clinical or research cohorts based on trans or homozygous status and age or cancer-follow-up criteria; BS2 is Supporting at 1 point, Moderate at 2 points, and Strong at 4 or more points.
ENIGMA Appendix H explicitly excludes homozygotes observed in gnomAD frequency data from BS2 application because those observations are captured by BA1 or BS1.
The available gnomAD data report zero homozygotes, but do not provide the required clinical cohort phenotype, phase, age, follow-up, or Fanconi Anemia information.
Still missing
No qualifying phenotyped clinical or research cohort observation was available for BS2 point assignment.
No phase information with a BRCA2 pathogenic or likely pathogenic variant was available.
No age at cancer diagnosis or age at last follow-up and no Fanconi Anemia phenotype assessment was available.
No variant-specific row for c.6444T>C, p.Ser2148=, or p.S2148= was found in Specifications_V1.2_2024-11-18.docx.txt.
No variant-specific row for c.6444T>C, p.Ser2148=, or p.S2148= was found in Appendices_V1.2_2024-11-18.docx.txt.
No variant-specific row for c.6444T>C, p.Ser2148=, or p.S2148= was found in HUMU-40-1557-s001.xlsx.txt.
BS3Not assessed: no variant-specific benign functional assay or governing ENIGMA Table 9 entry was found for c.6444T>C (p.Ser2148=).
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Reasoning
The ENIGMA BRCA1/2 specification requires BS3 functional evidence to come from well-established assays showing no damaging effect, with protein-only or combined mRNA/protein assays eligible and calibrated strength assigned through Table 9; conflicting well-established results must not be used. Searches of Specifications_Table9_V1.2_2024-11-18.xlsx.txt, Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, and HUMU-40-1557-s001.xlsx.txt found no entry for c.6444T>C, p.Ser2148=, or p.S2148=. The case evidence bundle contains no variant-specific benign functional assay result or relevant functional publication, so BS3 cannot be assigned.
Rule
Well-established in vitro or in vivo functional studies showing no damaging effect on protein function; apply BS3 for assays measuring protein function only or mRNA and protein combined, using calibrated VCEP Table 9 recommendations and excluding unexplained conflicting results.
Evidence considered
ENIGMA BRCA1/2 v1.2 specifies BS3 for well-established in vitro or in vivo functional studies showing no damaging effect on protein function; protein-only or combined mRNA/protein assays are eligible, and Table 9 provides calibrated recommendations.
The governing VCEP full-text files were searched under all three requested variant notations: c.6444T>C, p.Ser2148=, and p.S2148=; no matching functional-assay row was found.
The case bundle reports no variant-specific functional assay finding for BRCA2 c.6444T>C (p.Ser2148=), and the extracted publications are not functional studies of this variant.
Still missing
No entry for c.6444T>C, p.Ser2148=, or p.S2148= in Specifications_Table9_V1.2_2024-11-18.xlsx.txt.
No entry for c.6444T>C, p.Ser2148=, or p.S2148= in Specifications_V1.2_2024-11-18.docx.txt.
No entry for c.6444T>C, p.Ser2148=, or p.S2148= in Appendices_V1.2_2024-11-18.docx.txt.
No entry for c.6444T>C, p.Ser2148=, or p.S2148= in HUMU-40-1557-s001.xlsx.txt.
No variant-specific benign functional assay result is present in the case evidence bundle or its fetched paper extracts.
BS4Not assessed: no affected-relative non-segregation data or quantitative LR was available, so ENIGMA BS4 thresholds of 0.48, 0.23, 0.05, and 0.00285 cannot be applied.
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Reasoning
No variant-specific non-segregation in affected relatives, parental testing result, pedigree, meiosis count, or quantitative co-segregation likelihood ratio was identified for NM_000059.4:c.6444T>C (NP_000050.3:p.(Ser2148=)). ENIGMA assigns BS4 Supporting at LR ≤0.48, Moderate at LR ≤0.23, Strong at LR ≤0.05, and Very Strong at LR ≤0.00285; no LR is available to meet any threshold. The searched HUMU-40-1557-s001 converted text had no entry for c.6444T>C, p.Ser2148=, or p.S2148=; SupplementaryTables_V1.2.xlsx full text is unavailable and remains a lookup gap.
Rule
Apply BS4 only from quantitative lack-of-segregation analysis under ENIGMA V1.2 thresholds.
Evidence considered
The case evidence bundle and directly reviewed case evidence contain no variant-specific affected-relative non-segregation, parental testing, pedigree, or quantitative BS4 LR result for NM_000059.4:c.6444T>C.
ENIGMA V1.2 BS4 requires quantitative co-segregation analysis: Supporting LR ≤0.48, Moderate LR ≤0.23, Strong LR ≤0.05, and Very Strong LR ≤0.00285.
The on-record HUMU-40-1557-s001 VCEP text was searched under c.6444T>C, p.Ser2148=, and p.S2148=; no matching variant entry was found.
Still missing
No variant-specific affected-relative non-segregation, pedigree, parental testing, meiosis count, or quantitative BS4 LR was found in the case evidence.
HUMU-40-1557-s001 was searched for c.6444T>C, p.Ser2148=, and p.S2148= with no entry found.
SupplementaryTables_V1.2.xlsx is declared by the BRCA2 VCEP index for BS4, but its full text was unavailable for conversion; this is a file-access gap, not evidence of absence.
BP5Not assessed: no exact-variant multifactorial LR was available for comparison with the BP5 Supporting threshold of <=0.48.
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Reasoning
The ENIGMA BP5 rule is restricted to combined multifactorial likelihood evidence against pathogenicity and uses the explicitly downward thresholds Supporting LR <=0.48, Moderate LR <=0.23, Strong LR <=0.05, and Very Strong LR <=0.00285. The exact-variant clinical-history LR table was searched under all requested notations, but no LR was found, so no substituted value can be written as an inequality. The ClinVar Likely benign expert-panel classification is relevant to BP6, not a multifactorial LR for BP5. BP5 is therefore not assessed.
Rule
Use only combined multifactorial likelihood clinical data against pathogenicity; Supporting LR <=0.48:1, Moderate LR <=0.23:1, Strong LR <=0.05:1, Very Strong LR <=0.00285:1.
Evidence considered
The ENIGMA BP5 rules literally use downward comparisons: Supporting LR <=0.48:1, Moderate LR <=0.23:1, Strong LR <=0.05:1, and Very Strong LR <=0.00285:1.
Because the exact-variant LR is unavailable, no numeric inequality such as ‘value <= threshold’ can be evaluated and BP5 cannot be called met or not_met.
The exact ClinVar expert-panel Likely benign result is classified under BP6 in this group and was not misused as a BP5 multifactorial LR.
Still missing
No exact-variant entry found in PMID_31853058_BRCA2_clinical_history_LR.xlsx after searching c.6444T>C, p.Ser2148=, and p.S2148=.
No exact LR was available for the required explicit comparison value <= threshold.
Not applicable · 12· recorded as not applicableShow reasons ▾Hide reasons ▴PVS1N/ANot applicable: c.6444T>C is synonymous, not a VCEP-defined null variant, and SpliceAI max delta is 0.01.
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Reasoning
PVS1 is not applicable. The governing ENIGMA BRCA2 VCEP framework limits PVS1 to null variants such as nonsense, frameshift, canonical +/-1,2 splice-site, initiation-codon, or exon-deletion variants, with strength assigned through its exon-specific decision tree. NM_000059.4:c.6444T>C is a synonymous coding variant, NP_000050.3:p.(Ser2148=), and is not a protein-truncating or canonical splice-site variant. The case evidence reports SpliceAI max delta 0.01, below the VCEP no-impact splice threshold of 0.1, with no mRNA evidence establishing a loss-of-function transcript. Therefore no PVS1 strength tier applies; the generic ClinGen PVS1 framework is not used because the BRCA2 VCEP specification governs.
Rule
ENIGMA BRCA2 VCEP v1.2 PVS1 null-variant rule and VCEP PVS1 decision tree; synonymous variants are outside the defined PVS1 variant classes.
Evidence considered
The ENIGMA BRCA2 VCEP specification defines PVS1 for null variants and directs application through the VCEP PVS1 flowchart and exon-specific Table 4; it does not define synonymous substitutions as PVS1-eligible null variants.
Case normalization identifies NM_000059.4:c.6444T>C as NP_000050.3:p.(Ser2148=) / p.(S2148=), with consequence class synonymous.
Case SpliceAI result is max delta 0.01, and the VCEP specification uses SpliceAI <=0.1 as no predicted splice impact in its bioinformatic rules.
The governing VCEP files were searched for c.6444T>C, p.Ser2148=, and p.S2148=; no variant-specific pre-assigned PVS1 entry was found.
Still missing
No variant-specific entry was found when searching Specifications_V1.2_2024-11-18.docx.txt for c.6444T>C, p.Ser2148=, and p.S2148=.
No variant-specific entry was found when searching Appendices_V1.2_2024-11-18.docx.txt for c.6444T>C, p.Ser2148=, and p.S2148=.
No variant-specific entry was found when searching Specifications_Table4_V1.2_2024-11-18.xlsx.txt for c.6444T>C, p.Ser2148=, and p.S2148=.
No variant-specific entry was found when searching PMID_22505045_Houdayer_2012_HumMutat.pdf.txt for c.6444T>C, p.Ser2148=, and p.S2148=.
PS1N/ANot applicable: the variant is synonymous, and SpliceAI maximum delta 0.01 shows no qualifying splice event for PS1.
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Reasoning
The variant is synonymous (NM_000059.4:c.6444T>C; p.Ser2148=), not a missense substitution. The ENIGMA specification permits PS1 for a same-missense substitution or for a precisely matching pathogenic splice event; SpliceAI predicts no significant splice impact (maximum delta 0.01), and no governing VCEP file contains an entry for c.6444T>C, p.Ser2148=, or p.S2148=.
Rule
ENIGMA PS1 applies to the same missense substitution as a known pathogenic/likely pathogenic variant or to an exactly matching pathogenic splice event; SpliceAI must not show a qualifying splice effect for protein-change application.
Evidence considered
ENIGMA BRCA2 specification v1.2 defines PS1 for a previously established pathogenic or likely pathogenic same-missense substitution, or for an exactly matching predicted splice event; it does not provide a qualifying synonymous protein-change application here.
The case normalization is NM_000059.4:c.6444T>C, NP_000050.3:p.(Ser2148=)/p.(S2148=), with synonymous consequence.
SpliceAI is available and reports DS_AG 0.00, DS_AL 0.01, DS_DG 0.00, DS_DL 0.00; maximum delta score is 0.01, below the VCEP splice-impact threshold of 0.1.
Still missing
No entry for c.6444T>C, p.Ser2148=, or p.S2148= was found in Specifications_V1.2_2024-11-18.docx.txt.
No entry for c.6444T>C, p.Ser2148=, or p.S2148= was found in Appendices_V1.2_2024-11-18.docx.txt.
No entry for c.6444T>C, p.Ser2148=, or p.S2148= was found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt.
PS2VCEPNot applicable: ENIGMA explicitly prohibits PS2 because de novo occurrences lack calibrated predictive value for BRCA2-related cancers.
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Reasoning
The ENIGMA BRCA2 VCEP specification explicitly states that PS2 should not be used because BRCA1/2-related cancers are relatively common and the predictive capacity of de novo occurrences has not been calibrated.
VCEP rule
Do not use PS2 for BRCA2 under ENIGMA V1.2.
Evidence considered
ENIGMA BRCA1/2 Specification V1.2 Table 1 states for PS2: do not use; BRCA1/2-related cancers occur relatively commonly and no information is available to calibrate the predictive capacity of de novo occurrences.
PM1VCEPNot applicable: ENIGMA excludes PM1, and residue Ser2148 lies outside the approved domains aa 10-40 and aa 2481-3186.
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Reasoning
The governing ENIGMA BRCA2 specification explicitly marks PM1 as not applicable and states that domain information is incorporated into the calibrated BP1, BP4, and PP3 framework instead. The variant residue Ser2148 lies outside the authoritative BRCA2 domains listed in the governing materials: PALB2-binding domain aa 10-40 and DNA-binding domain aa 2481-3186; vcep_materials.json has no domain_tables entry for BRCA2.
VCEP rule
ENIGMA BRCA2 PM1 is not applicable; domain effects are evaluated through BP1, BP4, and PP3 using the approved BRCA2 domains.
Evidence considered
ENIGMA specification v1.2 marks PM1 as not applicable and directs domain-related interpretation to BP1, BP4, and PP3.
The governing domain definitions list BRCA2 PALB2 binding aa 10-40 and BRCA2 DNA binding aa 2481-3186; residue 2148 is in neither interval.
vcep_materials.json reports domain_tables as an empty object, so no additional gene-specific domain table supersedes the governing specification's complete domain list.
Still missing
No entry for c.6444T>C, p.Ser2148=, or p.S2148= was found in Specifications_V1.2_2024-11-18.docx.txt.
No entry for c.6444T>C, p.Ser2148=, or p.S2148= was found in Appendices_V1.2_2024-11-18.docx.txt.
No entry for c.6444T>C, p.Ser2148=, or p.S2148= was found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt.
PM4VCEPNot applicable: the variant is synonymous, p.(Ser2148=), with no protein-length change, and ENIGMA marks PM4 not applicable.
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Reasoning
PM4 is not applicable. The ENIGMA BRCA2 VCEP specification explicitly marks PM4 as not applicable and states that protein-length changes due to in-frame insertions/deletions or stop-loss variants are handled as part of bioinformatic analysis rather than assigned PM4. This variant is synonymous, p.(Ser2148=), so it produces no protein length change and is neither an in-frame indel nor a stop-loss variant.
VCEP rule
ENIGMA BRCA2 VCEP v1.2 PM4 rule: do not use; protein-length-change category is not applicable to a synonymous variant.
Evidence considered
The ENIGMA BRCA2 VCEP specification lists PM4 as do not use and describes the underlying PM4 category as in-frame insertion/deletion or stop-loss protein-length changes.
Case normalization identifies a synonymous change, NP_000050.3:p.(Ser2148=), which does not alter protein length.
The governing VCEP files were searched for c.6444T>C, p.Ser2148=, and p.S2148=; no variant-specific pre-assigned PM4 entry was found.
Still missing
No variant-specific entry was found when searching Specifications_V1.2_2024-11-18.docx.txt for c.6444T>C, p.Ser2148=, and p.S2148=.
No variant-specific entry was found when searching Appendices_V1.2_2024-11-18.docx.txt for c.6444T>C, p.Ser2148=, and p.S2148=.
No variant-specific entry was found when searching Specifications_Table4_V1.2_2024-11-18.xlsx.txt for c.6444T>C, p.Ser2148=, and p.S2148=.
No variant-specific entry was found when searching PMID_22505045_Houdayer_2012_HumMutat.pdf.txt for c.6444T>C, p.Ser2148=, and p.S2148=.
PM5N/ANot applicable: this is a synonymous variant, whereas ENIGMA PM5 is excluded for missense changes and reserved for PVS1 protein-termination variants.
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Reasoning
The conventional PM5 missense application is explicitly not applicable in the ENIGMA BRCA2 specification, and its repurposed PM5(PTC) application is restricted to protein-termination-codon variants meeting PVS1. This variant is synonymous, not a missense or PTC variant; no governing VCEP file contains a variant-specific entry.
Rule
ENIGMA conventional PM5 is not applicable; PM5(PTC) is limited to genomic PTC variants that meet PVS1.
Evidence considered
ENIGMA specification v1.2 marks conventional PM5 as not applicable because some residues can harbor pathogenic and non-pathogenic substitutions, and directs interpretation to BP1, BP4, and PP3.
ENIGMA's repurposed PM5(PTC) is limited to genomic protein-termination-codon variants annotated with PVS1 and uses exon-specific Table 4 weights.
The case consequence is synonymous (p.Ser2148=), so neither PM5 pathway applies.
Still missing
No entry for c.6444T>C, p.Ser2148=, or p.S2148= was found in Specifications_V1.2_2024-11-18.docx.txt.
No entry for c.6444T>C, p.Ser2148=, or p.S2148= was found in Appendices_V1.2_2024-11-18.docx.txt.
No entry for c.6444T>C, p.Ser2148=, or p.S2148= was found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt.
PM6VCEPNot applicable: ENIGMA explicitly prohibits PM6 because uncalibrated de novo occurrences do not provide usable BRCA2 evidence.
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Reasoning
The ENIGMA BRCA2 VCEP specification explicitly states that PM6 should not be used because BRCA1/2-related cancers are relatively common and the predictive capacity of de novo occurrences has not been calibrated, regardless of whether parental testing or paternity confirmation is available.
VCEP rule
Do not use PM6 for BRCA2 under ENIGMA V1.2.
Evidence considered
ENIGMA BRCA1/2 Specification V1.2 Table 1 states for PM6: do not use; BRCA1/2-related cancers occur relatively commonly and no information is available to calibrate the predictive capacity of de novo occurrences.
PP2VCEPNot applicable: ENIGMA excludes PP2 for BRCA2, and this variant is synonymous rather than missense.
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Reasoning
The governing ENIGMA BRCA2 specification explicitly marks PP2 as not applicable because missense variants are not a common mechanism of pathogenicity for BRCA1 and BRCA2. The queried variant is also synonymous rather than missense.
VCEP rule
ENIGMA BRCA2 PP2 is not applicable.
Evidence considered
ENIGMA specification v1.2 marks PP2 as not applicable and states that missense variants are not a common mechanism of pathogenicity for BRCA1 and BRCA2.
The case consequence is synonymous: NM_000059.4:c.6444T>C, NP_000050.3:p.(Ser2148=).
BP2VCEPNot applicable: the ENIGMA BRCA2 VCEP explicitly prohibits BP2 and permits it only in the context of BS2.
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Reasoning
The ENIGMA BRCA2 VCEP specification explicitly states that BP2 is not to be used and is applied only in the context of BS2. Accordingly, observations of this synonymous variant in trans with a pathogenic variant or in cis with a pathogenic variant do not produce BP2 under the governing framework. The governing Specifications_V1.2_2024-11-18.docx.txt was searched for c.6444T>C, p.Ser2148=, and p.S2148=; no variant-specific BP2 entry was found.
VCEP rule
Do not use; applied only in the context of BS2.
Evidence considered
ENIGMA BRCA2 VCEP BP2 rule: Do not use; applied only in the context of BS2.
Specifications_V1.2_2024-11-18.docx.txt was searched for c.6444T>C, p.Ser2148=, and p.S2148=; no variant-specific BP2 entry was found.
Still missing
No variant-specific entry for c.6444T>C, p.Ser2148=, or p.S2148= was found in Specifications_V1.2_2024-11-18.docx.txt after searching all three notations.
BP3VCEPNot applicable: BP3 is VCEP-excluded, and c.6444T>C is a synonymous substitution rather than an in-frame insertion/deletion.
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Reasoning
BP3 is not applicable. The ENIGMA BRCA2 VCEP specification explicitly marks BP3 as not applicable and states that in-frame deletions/insertions in repetitive regions without known function are captured by bioinformatic prediction and domain analysis instead. NM_000059.4:c.6444T>C is a synonymous single-nucleotide substitution, p.(Ser2148=), not an in-frame deletion or insertion; repeat-region context therefore cannot satisfy BP3.
VCEP rule
ENIGMA BRCA2 VCEP v1.2 BP3 rule: do not use; BP3 is limited to in-frame insertions/deletions in repetitive regions without known function.
Evidence considered
The ENIGMA BRCA2 VCEP specification lists BP3 as do not use and limits the underlying category to in-frame deletions/insertions in repetitive regions without known function.
Case normalization identifies a synonymous single-nucleotide substitution, NP_000050.3:p.(Ser2148=), not an in-frame insertion or deletion.
The governing VCEP files were searched for c.6444T>C, p.Ser2148=, and p.S2148=; no variant-specific pre-assigned BP3 entry was found.
Still missing
No variant-specific entry was found when searching Specifications_V1.2_2024-11-18.docx.txt for c.6444T>C, p.Ser2148=, and p.S2148=.
No variant-specific entry was found when searching Appendices_V1.2_2024-11-18.docx.txt for c.6444T>C, p.Ser2148=, and p.S2148=.
No variant-specific entry was found when searching Specifications_Table4_V1.2_2024-11-18.xlsx.txt for c.6444T>C, p.Ser2148=, and p.S2148=.
No variant-specific entry was found when searching PMID_22505045_Houdayer_2012_HumMutat.pdf.txt for c.6444T>C, p.Ser2148=, and p.S2148=.
BP4 is not applicable under the governing ENIGMA BRCA2 framework for this synonymous variant because its silent-variant BP4 pathway is restricted to variants inside a potentially clinically important functional domain. The encoded residue is Ser2148, outside the BRCA2 PALB2-binding domain (aa 10-40) and DNA-binding domain (aa 2481-3186). The available SpliceAI max delta is 0.01, but that score does not make an out-of-scope BP4 criterion applicable. No variant-specific BP4 pre-assignment was found in Specifications_V1.2_2024-11-18.docx, Appendices_V1.2_2024-11-18.docx, or PMID_22505045_Houdayer_2012_HumMutat.pdf.
Rule
ENIGMA v1.2 BP4: silent variant inside a specified BRCA2 functional domain with no predicted splice impact (SpliceAI <=0.1).
Evidence considered
ENIGMA v1.2 restricts silent-variant BP4 to variants inside a potentially clinically important functional domain and requires SpliceAI <=0.1.
ENIGMA defines BRCA2 functional domains relevant here as PALB2 binding aa 10-40 and DNA binding aa 2481-3186.
The synonymous consequence is p.(Ser2148=), and Ser2148 is outside both specified BRCA2 domains; SpliceAI max delta is 0.01.
Still missing
No variant-specific BP4 entry was found in Specifications_V1.2_2024-11-18.docx.
No variant-specific BP4 entry was found in Appendices_V1.2_2024-11-18.docx.
No variant-specific BP4 entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.
BP7N/ANot applicable: BP7 requires a silent variant inside an ENIGMA BRCA2 functional domain with BP4 met, but Ser2148 is outside both domains.
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Reasoning
Although the variant is synonymous, ENIGMA BRCA2 v1.2 applies BP7 to a silent variant only when it is inside a potentially clinically important functional domain and BP4 is met. Ser2148 is outside the specified BRCA2 PALB2-binding domain (aa 10-40) and DNA-binding domain (aa 2481-3186), so BP7 is not applicable. SpliceAI max delta 0.01 is below the no-impact threshold, but cannot overcome the governing location prerequisite. No variant-specific BP7 pre-assignment was found in Specifications_V1.2_2024-11-18.docx, Appendices_V1.2_2024-11-18.docx, or PMID_22505045_Houdayer_2012_HumMutat.pdf.
Rule
ENIGMA v1.2 BP7: silent variant inside a specified BRCA2 functional domain with BP4 met; nucleotide conservation is not considered.
Evidence considered
ENIGMA v1.2 requires BP7 for a silent variant inside a potentially clinically important functional domain only if BP4 is met.
The variant is p.(Ser2148=); Ser2148 is outside the specified BRCA2 PALB2-binding aa 10-40 and DNA-binding aa 2481-3186 domains.
SpliceAI max delta is 0.01, but the domain prerequisite for BP7 is not satisfied.
Still missing
No variant-specific BP7 entry was found in Specifications_V1.2_2024-11-18.docx.
No variant-specific BP7 entry was found in Appendices_V1.2_2024-11-18.docx.
No variant-specific BP7 entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.
AF 1.9e-05 · 30 / 1,592,250 alleles · 0 hom · FAF 8e-05
Middle Eastern1 / 5,928
0.00017
South Asian12 / 86,536
0.00014
Remaining individuals1 / 61,430
1.6e-05
European (non-Finnish)16 / 1,173,218
1.4e-05
0 alternate alleles recorded in 6 other groups: Admixed American, European (Finnish), Amish, East Asian, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 2.6e-05 · 6 / 230,326 alleles · 0 hom · FAF 7.5e-05
South Asian5 / 25,838
0.00019
European (non-Finnish)1 / 107,648
9.3e-06
0 alternate alleles recorded in 6 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.88413e-05; MAF= 0.00188%, 30/1592250 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.000168691; MAF= 0.01687%, 1/5928 alleles, homozygotes = 0); grpmax FAF= 7.973e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 2.605e-05; MAF= 0.00261%, 6/230326 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000193513; MAF= 0.01935%, 5/25838 alleles, homozygotes = 0); grpmax FAF= 7.548e-05.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
SpliceAI acceptor lossat +209 bp
0.010
SpliceAI acceptor gainat -25 bp
0.000
SpliceAI donor lossat +397 bp
0.000
SpliceAI donor gainat +47 bp
0.000
Pangolin splice lossmagnitude shown
-0.007
Pangolin splice gain
0.001
Other predictors
REVEL
Not available
BayesDel
Not available
How the predictions were used
PP3Not met: SpliceAI max delta 0.01 is below the ENIGMA PP3 threshold of 0.2 for predicted splicing in silent variants.
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Reasoning
The variant is synonymous, so the applicable computational path is SpliceAI rather than REVEL. ENIGMA BRCA1/2 Specification v1.2 applies PP3 to predicted splicing for silent variants at SpliceAI max delta >=0.2; the case SpliceAI result is max delta 0.01 (DS_AG 0.00, DS_AL 0.01, DS_DG 0.00, DS_DL 0.00), below the governing threshold. No variant-specific PP3 pre-assignment was found in Specifications_V1.2_2024-11-18.docx, Appendices_V1.2_2024-11-18.docx, or PMID_22505045_Houdayer_2012_HumMutat.pdf.
Rule
ENIGMA v1.2 PP3: silent variant with predicted splicing requires SpliceAI max delta >=0.2.
Evidence considered
ENIGMA BRCA1/2 Specification v1.2 states that PP3 applies to predicted splicing for silent variants at SpliceAI >=0.2.
SpliceAI reports DS_AG 0.00, DS_AL 0.01, DS_DG 0.00, and DS_DL 0.00; the maximum delta is 0.01.
The variant is NM_000059.4:c.6444T>C, p.(Ser2148=), a synonymous substitution, so REVEL is not the applicable predictor path.
Still missing
No variant-specific PP3 entry was found in Specifications_V1.2_2024-11-18.docx.
No variant-specific PP3 entry was found in Appendices_V1.2_2024-11-18.docx.
No variant-specific PP3 entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.
BP4 is not applicable under the governing ENIGMA BRCA2 framework for this synonymous variant because its silent-variant BP4 pathway is restricted to variants inside a potentially clinically important functional domain. The encoded residue is Ser2148, outside the BRCA2 PALB2-binding domain (aa 10-40) and DNA-binding domain (aa 2481-3186). The available SpliceAI max delta is 0.01, but that score does not make an out-of-scope BP4 criterion applicable. No variant-specific BP4 pre-assignment was found in Specifications_V1.2_2024-11-18.docx, Appendices_V1.2_2024-11-18.docx, or PMID_22505045_Houdayer_2012_HumMutat.pdf.
Rule
ENIGMA v1.2 BP4: silent variant inside a specified BRCA2 functional domain with no predicted splice impact (SpliceAI <=0.1).
Evidence considered
ENIGMA v1.2 restricts silent-variant BP4 to variants inside a potentially clinically important functional domain and requires SpliceAI <=0.1.
ENIGMA defines BRCA2 functional domains relevant here as PALB2 binding aa 10-40 and DNA binding aa 2481-3186.
The synonymous consequence is p.(Ser2148=), and Ser2148 is outside both specified BRCA2 domains; SpliceAI max delta is 0.01.
Still missing
No variant-specific BP4 entry was found in Specifications_V1.2_2024-11-18.docx.
No variant-specific BP4 entry was found in Appendices_V1.2_2024-11-18.docx.
No variant-specific BP4 entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.
BP7N/ANot applicable: BP7 requires a silent variant inside an ENIGMA BRCA2 functional domain with BP4 met, but Ser2148 is outside both domains.
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Reasoning
Although the variant is synonymous, ENIGMA BRCA2 v1.2 applies BP7 to a silent variant only when it is inside a potentially clinically important functional domain and BP4 is met. Ser2148 is outside the specified BRCA2 PALB2-binding domain (aa 10-40) and DNA-binding domain (aa 2481-3186), so BP7 is not applicable. SpliceAI max delta 0.01 is below the no-impact threshold, but cannot overcome the governing location prerequisite. No variant-specific BP7 pre-assignment was found in Specifications_V1.2_2024-11-18.docx, Appendices_V1.2_2024-11-18.docx, or PMID_22505045_Houdayer_2012_HumMutat.pdf.
Rule
ENIGMA v1.2 BP7: silent variant inside a specified BRCA2 functional domain with BP4 met; nucleotide conservation is not considered.
Evidence considered
ENIGMA v1.2 requires BP7 for a silent variant inside a potentially clinically important functional domain only if BP4 is met.
The variant is p.(Ser2148=); Ser2148 is outside the specified BRCA2 PALB2-binding aa 10-40 and DNA-binding aa 2481-3186 domains.
SpliceAI max delta is 0.01, but the domain prerequisite for BP7 is not satisfied.
Still missing
No variant-specific BP7 entry was found in Specifications_V1.2_2024-11-18.docx.
No variant-specific BP7 entry was found in Appendices_V1.2_2024-11-18.docx.
No variant-specific BP7 entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
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
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.
The ACMG/AMP standards paper provides general variant-classification guidance but no exact-variant evidence for BRCA2 c.6444T>C / p.S2148=.
The variant classification approach described in this paper is meant to be applicable to variants in all Mendelian genes whether identified by single gene tests, multi-gene panels, exome sequencing or genome sequencing.
Proposed Criteria for Interpretation of Sequence Variants, paragraph 2
A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.
The paper describes a general rules-based variant scoring system and does not mention BRCA2 c.6444T>C or provide variant-specific evidence.
Over 16,500 pathogenicity assessments on 11,894 distinct variants in 338 genes causing neurological, endocrine, and nephrotic genetic disorders were performed on the sequencing data.
Materials and Methods, Data Collection and Storage
The emerging landscape of breast cancer susceptibility.
Stratton MR et al. · 2008
The paper discusses BRCA2 as a high-penetrance breast-cancer susceptibility gene but does not report c.6444T>C or p.S2148= and supplies no exact-variant phenotype or prevalence evidence.
Disease-causing mutations in BRCA1 and BRCA2 result in inactivation of the encoded proteins, generally by causing premature protein truncation or nonsense-mediated RNA decay.
Rare high-penetrance breast cancer susceptibility genes, page 17
NSGC practice guideline: risk assessment and genetic counseling for hereditary breast and ovarian cancer.
The guideline discusses BRCA2-associated cancer risk generally and does not report c.6444T>C or p.S2148= or provide exact-variant phenotype evidence.
Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics.
The paper lists BRCA1 and BRCA2 as hereditary breast and ovarian cancer genes but does not report the exact variant or provide PS4, PP4, or BP5 evidence.
Hereditary breast and ovarian cancer ... BRCA1 BRCA2 ... AD ... KP and EP
Table 1, ACMG SF v2.0 genes and associated phenotypes
ACMG SF v3.0 list for reporting of secondary findings in clinical exome and genome sequencing: a policy statement of the American College of Medical Genetics and Genomics (ACMG).
The paper does not report or analyze BRCA2 c.6444T>C or p.S2148= and provides no variant-specific clinical, segregation, case-control, or population evidence.
Management of risk in individuals heterozygous for pathogenic PALB2 variants is similar to that for the BRCA1 and BRCA2 genes; however, given the overall lower range of PALB2-associated risk in breast and ovarian cancer, individualized estimates are important for management decisions.
Considerations for Specific Phenotype Categories, genes related to cancer phenotypes, PALB2 discussion
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
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= 1.88413e-05; MAF= 0.00188%, 30/1592250 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.000168691; MAF= 0.01687%, 1/5928 alleles, homozygotes = 0); grpmax FAF= 7.973e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 2.605e-05; MAF= 0.00261%, 6/230326 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000193513; MAF= 0.01935%, 5/25838 alleles, homozygotes = 0); grpmax FAF= 7.548e-05.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Likely benign (6 clinical laboratories) 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 = 415692)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
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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