BRCA2 c.7484T>C, p.(Ile2495Thr)

Reasoning

NM_000059.4:c.7484T>C is a missense variant, p.(Ile2495Thr), in the BRCA2 DNA-binding domain (amino acids 2481-3186). Under the ENIGMA BRCA2 V1.2 framework, computational evidence is evaluated using the missense protein-impact path for this consequence. The case-specific REVEL score is 0.663, which meets the supplied ClinGen SVI REVEL supporting threshold of >=0.644 (Pejaver et al. 2022, PMID:36413997), so PP3 Supporting is met. SpliceAI is not used to support PP3 for this missense substitution.

Rule

Missense variant: use REVEL only; PP3 Supporting at REVEL >=0.644 under the supplied ClinGen SVI calibration (Pejaver et al. 2022, PMID:36413997).

Evidence considered

• The ENIGMA BRCA1/2 V1.2 specification defines PP3 for predicted deleterious computational impact and identifies the BRCA2 DNA-binding domain as a clinically important functional domain.
• The case-specific REVEL lookup reports a score of 0.663 for BRCA2 c.7484T>C (p.Ile2495Thr).
• The supplied ClinGen SVI REVEL calibration assigns PP3 Supporting at REVEL >=0.644 (Pejaver et al. 2022, PMID:36413997).
• The ENIGMA supplementary functional-prediction table contains the exact variant entry c.7484T>C / p.(Ile2495Thr) in the BRCA2 DNA-binding domain, confirming the governing variant match; its listed BayesDel value is not substituted for the missense REVEL path used here.

Sources

Reasoning

BS3 Strong is met by the governing ENIGMA BRCA2 V1.2 Table 9 pre-assignment for the exact variant c.7484T>C (p.Ile2495Thr; p.I2495T). The row states that two calibrated studies showed protein function similar to benign control variants: Mesman et al. (PMID:29988080) reported complementation, HDR activity of 58% relative to wild type, and cisplatin sensitivity of 84% relative to wild type; Richardson et al. (PMID:33609447) reported a neutral result. Mesman used an mESC complementation assay after loss of endogenous Brca2, an I-Sce1-induced HDR reporter, and cisplatin sensitivity, providing biologically relevant protein/cellular functional testing with calibrated controls. ENIGMA Table 9 is the governing pre-assigned answer and outranks independent threshold calculation.

Rule

ENIGMA BRCA2 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 only or mRNA and protein combined; Table 9 provides calibrated code recommendations.

Evidence considered

• Specifications_Table9_V1.2_2024-11-18.xlsx: the exact c.7484T>C / p.(Ile2495Thr) row pre-assigns BS3 Strong and records two calibrated studies, Mesman 2019 (PMID:29988080) and Richardson 2021 (PMID:33609447), with benign/neutral functional results.
• Mesman et al. (PMID:29988080), Table 2 and Fig. 3b: c.7484T>C p.Ile2495Thr complemented the mESC phenotype after endogenous Brca2 loss; HDR was 58% and cisplatin sensitivity was 84% relative to wild type.
• ENIGMA Appendix E states that PS3 and BS3 are reserved for protein-function assays, that the selected mammalian assays were calibrated against clinically classified reference variants, and that no functional impact without conflicting damaging evidence supports Strong benign evidence.

Sources

Reasoning

The ENIGMA BRCA1/2 VCEP specification permits PS1 for a missense substitution only when a previously classified pathogenic variant produces the same amino-acid change through a different nucleotide change and has no predicted or confirmed splice effect. Searches of Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, and Specifications_Table4_V1.2_2024-11-18.xlsx.txt found no entry for c.7484T>C, p.Ile2495Thr, or p.I2495T, and the available case evidence provides no qualifying pathogenic same-amino-acid comparator. Therefore PS1 is not met.

Rule

ENIGMA BRCA1/2 V1.2 PS1: same missense amino-acid substitution as a previously classified pathogenic variant, with no confirmed or predicted splice effect.

Evidence considered

• ENIGMA specifies PS1 for a missense change only when a previously classified pathogenic variant produces the same amino-acid substitution via a different nucleotide change and has no confirmed or predicted splice effect.
• The three governing VCEP full-text files were searched for c.7484T>C, p.Ile2495Thr, and p.I2495T; no entry was found.

Still missing

• No entry for c.7484T>C, p.Ile2495Thr, or p.I2495T was found in Specifications_V1.2_2024-11-18.docx.txt.
• No entry for c.7484T>C, p.Ile2495Thr, or p.I2495T was found in Appendices_V1.2_2024-11-18.docx.txt.
• No entry for c.7484T>C, p.Ile2495Thr, or p.I2495T was found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt.
• No qualifying pathogenic same-amino-acid comparator is available in the reviewed case evidence.

Sources

Reasoning

PS3 is not met. The governing ENIGMA BRCA2 V1.2 Table 9 entry for BRCA2 c.7484T>C (p.Ile2495Thr; p.I2495T) assigns BS3 Strong, not PS3, based on two calibrated protein-function studies showing no damaging effect. Mesman et al. (PMID:29988080) tested the variant in an mESC BRCA2 complementation assay and reported complementation, 58% HDR activity relative to wild type, and 84% cisplatin sensitivity relative to wild type. The independent Table 9 study by Richardson et al. (PMID:33609447) is summarized as neutral. These results support benign functional evidence rather than a damaging effect.

Rule

ENIGMA BRCA2 V1.2: PS3 applies to well-established in vitro or in vivo functional studies supportive of a damaging effect when the assay measures protein only or mRNA and protein combined; calibrated variant-specific Table 9 assignments govern.

Evidence considered

• Specifications_Table9_V1.2_2024-11-18.xlsx: the exact c.7484T>C / p.(Ile2495Thr) row assigns BS3 Strong and states that two calibrated studies show protein function similar to benign controls; the row identifies Mesman 2019 (PMID:29988080) and Richardson 2021 (PMID:33609447).
• Mesman et al. (PMID:29988080) reports complementation of the lethal phenotype after loss of endogenous mouse Brca2, 58% HDR capacity relative to wild-type BRCA2, and 84% cisplatin sensitivity relative to wild type for c.7484T>C p.Ile2495Thr.
• ENIGMA Appendix E reserves PS3 for protein-function assays showing a damaging effect and states that no impact in at least one calibrated study without conflict supports Strong benign evidence; the exact VCEP pre-assigned code governs here.

Sources

Reasoning

The ENIGMA BRCA2 VCEP specifies PM2 Supporting only when the variant is absent from gnomAD v2.1 non-cancer exomes and gnomAD v3.1 non-cancer genomes, with regional read depth at least 25. This variant is observed in both required datasets: 2/236,916 alleles in gnomAD v2.1 non-cancer exomes (AF 8.44181e-06) and 1/147,990 alleles in gnomAD v3.1 non-cancer genomes (AF 6.75721e-06). Because it is not absent from either required control dataset, PM2 is not met regardless of the unreported depth value.

Rule

PM2 Supporting: apply only when absent from gnomAD v2.1 non-cancer exomes and gnomAD v3.1 non-cancer genomes, with regional average read depth >=25 and acceptable quality.

Evidence considered

• The ENIGMA specification requires absence from gnomAD v2.1 non-cancer exomes and gnomAD v3.1 non-cancer genomes, with regional read depth >=25, for PM2 Supporting.
• GNOMAD_V2_1_NON_CANCER reports 2/236,916 non-cancer exome alleles and GNOMAD_V3_1_NON_CANCER reports 1/147,990 non-cancer genome alleles; the variant is therefore not absent from controls.
• The exact variant row was found in HUMU-40-1557-s001.xlsx.txt as BRCA2 c.7484T>C, p.(Ile2495Thr), but the row does not establish PM2 absence.

Still missing

• No variant-specific row for c.7484T>C, p.Ile2495Thr, or p.I2495T was found in Specifications_V1.2_2024-11-18.docx.txt; its general PM2 rule was found and applied.
• No variant-specific row for c.7484T>C, p.Ile2495Thr, or p.I2495T was found in Appendices_V1.2_2024-11-18.docx.txt; its general Appendix G PM2 rule was found and applied.
• Regional read depth is not reported in the available non-cancer evidence, but depth cannot change the conclusion because the variant is present in both required datasets.

Sources

Reasoning

The exact ClinVar record for NM_000059.4(BRCA2):c.7484T>C (p.Ile2495Thr) has expert_panels: {} and review status limited to conflicting single-submitter laboratory assertions. The available Likely benign assertions are not expert-panel classifications and cannot trigger PP5. ENIGMA's specification also says PP5 is not for use. No pathogenic or likely pathogenic exact-variant ClinVar expert-panel classification exists in the reviewed record.

Rule

Apply only to an exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification; none is present, and ENIGMA specifies PP5 is not for use.

Evidence considered

• ClinVar variation 52342 exactly matches NM_000059.4(BRCA2):c.7484T>C (p.Ile2495Thr), but source_data.expert_panels is empty and the record has conflicting single-submitter classifications.
• The ENIGMA specification states for PP5: "Do not use."

Sources

Reasoning

The ENIGMA BRCA2 VCEP specifies BA1 when filter allele frequency exceeds 0.001 (0.1%) in the preferred non-founder population datasets. The required gnomAD v2.1 non-cancer exome data show 2/236,916 alleles, AF 8.44181e-06, with maximum exome FAF 3.23e-06; the gnomAD v3.1 non-cancer genome data show 1/147,990 alleles, AF 6.75721e-06, with genome FAF 0. Both are far below 0.001, so BA1 is not met. The all-comers gnomAD v4.1 value was not used because the governing VCEP specifies gnomAD v2.1 non-cancer exomes and gnomAD v3.1 non-cancer genomes.

Rule

BA1: apply stand-alone benign evidence when filter allele frequency is >0.001 in gnomAD v2.1 non-cancer exomes and/or gnomAD v3.1 non-cancer genomes, using non-founder populations and adequate quality/depth.

Evidence considered

• The ENIGMA specification sets BA1 at filter allele frequency >0.001 and requires gnomAD v2.1 non-cancer exomes and/or gnomAD v3.1 non-cancer genomes.
• GNOMAD_V2_1_NON_CANCER reports 2/236,916 non-cancer exome alleles, AF 8.44181e-06, maximum exome FAF 3.23e-06, and zero homozygotes.
• GNOMAD_V3_1_NON_CANCER reports 1/147,990 non-cancer genome alleles, AF 6.75721e-06, genome FAF 0, and zero homozygotes.
• The exact variant row in HUMU-40-1557-s001.xlsx.txt reports c.7484T>C/p.(Ile2495Thr), but its older gnomAD frequency column is not substituted for the governing VCEP FAF dataset.

Still missing

• No variant-specific row for c.7484T>C, p.Ile2495Thr, or p.I2495T was found in Specifications_V1.2_2024-11-18.docx.txt; its general BA1 rule was found and applied.
• No variant-specific row for c.7484T>C, p.Ile2495Thr, or p.I2495T was found in Appendices_V1.2_2024-11-18.docx.txt; its general Appendix G BA1 rule was found and applied.

Sources

Reasoning

The ENIGMA BRCA2 VCEP specifies BS1 Strong for filter allele frequency >0.0001 and BS1 Supporting for >0.00002 to <=0.0001 in gnomAD v2.1 non-cancer exomes and/or gnomAD v3.1 non-cancer genomes. The required non-cancer datasets show maximum FAF values of 3.23e-06 for gnomAD v2.1 non-cancer exomes and 0 for gnomAD v3.1 non-cancer genomes. Both are below the lowest BS1 threshold of >0.00002, so BS1 is not met.

Rule

BS1: apply Strong when FAF >0.0001 or Supporting when FAF >0.00002 and <=0.0001 in gnomAD v2.1 non-cancer exomes and/or gnomAD v3.1 non-cancer genomes, using non-founder populations and adequate quality/depth.

Evidence considered

• The ENIGMA specification sets BS1 Strong at FAF >0.0001 and BS1 Supporting at FAF >0.00002 to <=0.0001, using gnomAD v2.1 non-cancer exomes and/or gnomAD v3.1 non-cancer genomes.
• GNOMAD_V2_1_NON_CANCER reports maximum exome FAF 3.23e-06; GNOMAD_V3_1_NON_CANCER reports genome FAF 0.
• The exact HUMU-40-1557-s001.xlsx.txt row lists gnomAD MAF 2.5391021734714605e-05 and a frequency-derived moderate benign direction, but the governing ENIGMA rule requires filter allele frequency from the specified non-cancer datasets; the applicable FAF values remain below BS1 Supporting.

Still missing

• No variant-specific row for c.7484T>C, p.Ile2495Thr, or p.I2495T was found in Specifications_V1.2_2024-11-18.docx.txt; its general BS1 thresholds were found and applied.
• No variant-specific row for c.7484T>C, p.Ile2495Thr, or p.I2495T was found in Appendices_V1.2_2024-11-18.docx.txt; its general Appendix G BS1 thresholds were found and applied.

Sources

Reasoning

ENIGMA V1.2 permits BP1_Strong for a missense variant only when it is outside a potentially clinically important functional domain and has no predicted splicing impact. Residue 2495 is inside the ENIGMA BRCA2 DNA-binding domain at amino acids 2481-3186. Because the required outside-domain condition is not satisfied, BP1 is not met; no BP1 strength is assigned.

Rule

ENIGMA BRCA1/2 V1.2 BP1_Strong: missense variant outside a potentially clinically important functional domain and SpliceAI <=0.1.

Evidence considered

• ENIGMA V1.2 requires BP1_Strong to be outside a potentially clinically important functional domain and to have no predicted splicing impact.
• ENIGMA lists the BRCA2 DNA-binding domain as amino acids 2481-3186; residue 2495 is within this interval.

Sources

Reasoning

NM_000059.4:c.7484T>C is a missense variant, p.(Ile2495Thr), so BP4 must be assessed through the missense protein-impact path using REVEL rather than SpliceAI. The case-specific REVEL score is 0.663, exceeding the supplied ClinGen SVI BP4 supporting cutoff of <=0.29 and therefore not supporting a benign/no-impact computational conclusion. The SpliceAI max delta of 0.028 is not used to convert this missense result into BP4 evidence.

Rule

Missense variant: use REVEL only; BP4 Supporting requires REVEL <=0.29 under the supplied ClinGen SVI calibration (Pejaver et al. 2022, PMID:36413997).

Evidence considered

• The ENIGMA BRCA1/2 V1.2 specification defines BP4 as computational evidence for no impact and provides BRCA2 missense-domain guidance.
• The case-specific REVEL lookup reports a score of 0.663 for BRCA2 c.7484T>C (p.Ile2495Thr).
• The supplied ClinGen SVI REVEL calibration assigns BP4 Supporting at REVEL <=0.29 (Pejaver et al. 2022, PMID:36413997); 0.663 does not meet that threshold.
• SpliceAI reports a maximum delta of 0.028, but splice prediction is not substituted for the applicable REVEL missense path.

Sources

Reasoning

The exact ClinVar record for NM_000059.4(BRCA2):c.7484T>C (p.Ile2495Thr) has expert_panels: {} and contains only conflicting single-submitter laboratory assertions. The available Likely benign submissions are not exact-variant ClinVar expert-panel classifications and cannot trigger BP6. ENIGMA's specification also says BP6 is not for use. No benign or likely benign exact-variant ClinVar expert-panel classification exists in the reviewed record.

Rule

Apply only to an exact-variant ClinVar expert-panel Benign or Likely benign classification; none is present, and ENIGMA specifies BP6 is not for use.

Evidence considered

• ClinVar variation 52342 exactly matches NM_000059.4(BRCA2):c.7484T>C (p.Ile2495Thr), but source_data.expert_panels is empty; Likely benign entries are single-submitter clinical-laboratory assertions.
• The ENIGMA specification states for BP6: "Do not use."

Sources

Reasoning

The ENIGMA BRCA2 specification requires PS4 case-control evidence with p-value <=0.05, OR >=4, and a lower confidence interval excluding 2.0. The exact BRCA2 c.7484T>C / p.Ile2495Thr row in HUMU-40-1557-s001.xlsx has no case-control LR or OR/p-value entry; its combined LR is 0.7333055058687654, which is multifactorial likelihood evidence handled under PP4/BP5 rather than PS4. The source also records two Easton-dataset observations, but the ENIGMA specification says not to use proband counting as originally described. SupplementaryTables_V1.2.xlsx, which declares PS4, was unavailable as searchable full text, so no governing ST7 lookup could be completed.

Rule

Case-control studies; p-value <=0.05 and OR >=4 (lower confidence interval excludes 2.0).

Evidence considered

• ENIGMA Table 1 states: "Case-control studies; p-value <=0.05 and OR >=4 (lower confidence interval excludes 2.0)."
• The exact HUMU-40-1557-s001 row is BRCA2 c.7484T>C, p.(Ile2495Thr), with blank case-control LR and combined LR 0.7333055058687654; the same row records two Easton-dataset observations.
• ENIGMA states: "Do not use Proband Counting as originally described."

Still missing

• No qualifying case-control OR, p-value, and confidence interval was available for c.7484T>C in HUMU-40-1557-s001.xlsx.
• No exact-variant PS4 entry was found in Specifications_V1.2_2024-11-18.docx.txt after searching c.7484T>C, p.Ile2495Thr, and p.I2495T.
• SupplementaryTables_V1.2.xlsx declares PS4 but its full text was unavailable for search; this is a conversion gap, not evidence that the table is empty.

Sources

Reasoning

The ENIGMA BRCA2 VCEP specification restricts PM3 to a patient with a phenotype consistent with BRCA1/2-related Fanconi anemia and a co-occurrent variant in the same gene, with point-based weighting for pathogenic or likely pathogenic variants in trans or phase-unknown. The available case evidence does not document a Fanconi anemia phenotype, chromosome-breakage result, a pathogenic or likely pathogenic BRCA2 co-occurring variant, or phase; therefore no PM3 points or strength can be assigned. The exact-variant rows located in the governing VCEP full-text files concern functional or multifactorial data rather than a qualifying PM3 observation.

Rule

ENIGMA BRCA2 PM3_VariableWeight: apply only for a patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi anemia and a co-occurrent variant in the same gene; PM3_Supporting = 1 point, PM3 = 2 points, PM3_Strong = 4 or more points.

Evidence considered

• ENIGMA BRCA2 VCEP v1.2 specifies PM3 only for Fanconi anemia-consistent patients with co-occurring variants in BRCA1 or BRCA2; PM3 strength is based on Table 6 points from pathogenic/likely pathogenic variants in trans or phase-unknown.
• The consolidated case-evidence bundle and direct case JSON files contain no qualifying Fanconi anemia phenotype, chromosome-breakage result, same-gene pathogenic/likely pathogenic co-occurrence, or phase observation for c.7484T>C.
• The exact-variant VCEP searches found c.7484T>C / p.Ile2495Thr / p.I2495T in functional and multifactorial tables, but not in a PM3 allelic-observation entry.

Still missing

• The governing file Specifications_V1.2_2024-11-18.docx.txt was searched for c.7484T>C, p.Ile2495Thr, and p.I2495T; no variant-specific PM3 entry was found.
• The case evidence bundle does not provide a Fanconi anemia phenotype or chromosome-breakage result for a carrier of NM_000059.4:c.7484T>C.
• The case evidence bundle does not provide a same-gene pathogenic/likely pathogenic co-occurring variant, confirmed trans/cis phase, or sufficient phase-unknown proband observation for this variant.

Sources

Reasoning

The ENIGMA specification permits PP1 only from quantitative co-segregation analysis, with supporting evidence at LR ≥2.08, moderate at LR ≥4.3, strong at LR ≥18.7, and very strong at LR ≥350. The exact HUMU-40-1557-s001 row for BRCA2 c.7484T>C/p.(Ile2495Thr)/I2495T has a blank Segregation LR field; its combined LR is 0.7333055058687654 and is explicitly described as not <0.5 or >2, so it does not establish a PP1 segregation result. No variant-specific co-segregation or meiosis count was found in the searched case evidence or extracted literature. The designated SupplementaryTables_V1.2.xlsx full text was unavailable, so its BS4/PS4 table could not be independently searched.

Rule

Apply weight as per Bayes Score: PP1 LR ≥2.08:1; PP1_Moderate LR ≥4.3:1; PP1_Strong LR ≥18.7:1; PP1_Very Strong LR ≥350:1. LR >0.48 and <2.08 provides no supporting evidence in either direction.

Evidence considered

• ENIGMA BRCA1/2 VCEP Specifications v1.2, Table 1: PP1 is assigned from quantitative co-segregation analysis using LR thresholds of 2.08, 4.3, 18.7, and 350 for supporting, moderate, strong, and very strong evidence, respectively.
• HUMU-40-1557-s001 exact row for BRCA2 c.7484T>C, p.(Ile2495Thr), legacy I2495T: Segregation LR is blank; combined LR is 0.7333055058687654 and is labeled ‘Combined LR is not <0.5 or >2’.
• The case evidence bundle and its extracted paper findings contain no variant-specific parental testing, affected-relative segregation, meiosis count, or quantitative co-segregation result.

Still missing

• No variant-specific quantitative co-segregation LR, affected-relative meioses, or family pedigree data were found in the case evidence bundle.
• HUMU-40-1557-s001 was searched for c.7484T>C, p.Ile2495Thr, and p.I2495T; the exact row has a blank Segregation LR field.
• SupplementaryTables_V1.2.xlsx full text was unavailable and could not be independently searched.

Sources

Reasoning

The ENIGMA BRCA2 VCEP limits BS2 to qualifying healthy-adult or clinically phenotyped observations, including specified co-occurrence or homozygous presentations, and explicitly excludes homozygote observations from gnomAD frequency data. The available gnomAD non-cancer datasets report zero homozygotes, but they do not provide the required phenotyped clinical or research-cohort observations, age/follow-up, co-occurrence phase, or Fanconi-anemia assessment. Therefore BS2 cannot be assessed from the available evidence.

Rule

BS2: apply only from qualifying clinically or research-cohort phenotyped individuals meeting the ENIGMA Table 8/Appendix H age, phase, co-occurrence or homozygote, and Fanconi-anemia stipulations; do not use gnomAD frequency observations.

Evidence considered

• The ENIGMA specification and Appendix H require BS2 point-based evidence from phenotyped individuals and state that gnomAD homozygote observations must not be used for BS2.
• GNOMAD_V2_1_NON_CANCER and GNOMAD_V3_1_NON_CANCER each report zero homozygotes, which does not constitute a qualifying BS2 observation.

Still missing

• No variant-specific row for c.7484T>C, p.Ile2495Thr, or p.I2495T was found in Specifications_V1.2_2024-11-18.docx.txt; its general BS2 rule was found and applied.
• No variant-specific row for c.7484T>C, p.Ile2495Thr, or p.I2495T was found in Appendices_V1.2_2024-11-18.docx.txt; its general Appendix H BS2 rule was found and applied.
• No qualifying phenotyped clinical or research-cohort observations with age/follow-up, phase, co-occurrence, homozygous status, and Fanconi-anemia assessment were identified.

Sources

Reasoning

The ENIGMA specification permits BS4 only from quantitative lack-of-segregation analysis, with supporting evidence at LR ≤0.48, moderate at LR ≤0.23, strong at LR ≤0.05, and very strong at LR ≤0.00285. The exact HUMU-40-1557-s001 row for BRCA2 c.7484T>C/p.(Ile2495Thr)/I2495T has a blank Segregation LR field; the available combined LR is 0.7333055058687654, explicitly outside the informative benign range (>0.48 and <2 is neutral), and does not constitute a BS4 segregation LR. No variant-specific non-segregation, affected-relative genotype, or pedigree data were found. The designated SupplementaryTables_V1.2.xlsx full text was unavailable, so its BS4/PS4 table could not be independently searched.

Rule

Apply weight as per Bayes Score: BS4_Supporting LR ≤0.48:1; BS4_Moderate LR ≤0.23:1; BS4 LR ≤0.05:1; BS4_Very Strong LR ≤0.00285:1. LR >0.48 and <2.08 provides no supporting evidence in either direction.

Evidence considered

• ENIGMA BRCA1/2 VCEP Specifications v1.2, Table 1: BS4 is assigned from quantitative lack-of-segregation analysis using LR thresholds of ≤0.48, ≤0.23, ≤0.05, and ≤0.00285 for supporting, moderate, strong, and very strong evidence, respectively.
• HUMU-40-1557-s001 exact row for BRCA2 c.7484T>C, p.(Ile2495Thr), legacy I2495T: Segregation LR is blank; combined LR is 0.7333055058687654 and is labeled ‘Combined LR is not <0.5 or >2’, which is outside the informative BS4 range.
• The case evidence bundle and its extracted paper findings contain no variant-specific parental testing, affected-relative non-segregation, meiosis count, or quantitative BS4 result.

Still missing

• No variant-specific quantitative non-segregation LR, affected-relative genotype data, or family pedigree data were found in the case evidence bundle.
• HUMU-40-1557-s001 was searched for c.7484T>C, p.Ile2495Thr, and p.I2495T; the exact row has a blank Segregation LR field.
• SupplementaryTables_V1.2.xlsx full text was unavailable and could not be independently searched.

Sources