BRCA2 c.5857G>T, p.(Glu1953Ter)

Reasoning

NM_000059.4:c.5857G>T is a nonsense variant producing NP_000050.3:p.(Glu1953Ter) / p.(E1953*). BRCA2 loss of function is an established disease mechanism in the ENIGMA BRCA2 VCEP framework. The variant lies in exon 11, within the exon 11 coding interval c.1910-c.6841 and well before the terminal exon; the governing Specifications_Table4_V1.2_2024-11-18.xlsx assigns exon 11 protein-termination-codon variants PVS1, with no exon-11 downgrade or PVS1_N/A designation. The ENIGMA Specifications v1.2 therefore supports full-strength PVS1, reported here with the required literal strength word "very strong". The exact variant is also listed as c.5857G4T / p.Glu1953X among deleterious BRCA2 changes in the Dutch screening cohort, corroborating the nonsense consequence but not determining the VCEP strength.

Rule

ENIGMA BRCA2 VCEP v1.2 Specifications_Table4: exon 11 protein termination codon (PTC) variants are assigned PVS1; no downgrade applies.

Evidence considered

• The case normalization identifies NM_000059.4:c.5857G>T as NP_000050.3:p.(Glu1953Ter) / p.(E1953*), a nonsense consequence.
• The ENIGMA BRCA2 specification states that PVS1 variable weight applies to null variants in a gene where loss of function is a known disease mechanism and directs protein-termination-codon variants to exon-specific Table 4 weights.
• Specifications_Table4_V1.2_2024-11-18.xlsx lists BRCA2 exon 11 as PTC: PVS1; exon 11 spans c.1910-c.6841 and its PM5-PTC field is applicable, with no PVS1_N/A designation.
• The BRCA2 exon map in Appendices_V1.2_2024-11-18.docx places exon 11 within the coding transcript and identifies exon 27 as the terminal exon, supporting a truncating consequence before the terminal exon rather than a terminal-exon escape scenario.
• PMID:16683254 explicitly lists the same variant as c.5857G4T (6085G4T), p.Glu1953X, among deleterious BRCA2 changes identified in four Dutch hereditary breast/ovarian cancer families; this corroborates the variant-level nonsense annotation but is not used as a substitute for the VCEP rule.

Still missing

• No exact c.5857G>T, p.Glu1953Ter, or p.E1953* entry was found when searched in Specifications_V1.2_2024-11-18.docx.txt; its exon-level PVS1 rule governs.
• No exact c.5857G>T, p.Glu1953Ter, or p.E1953* entry was found when searched in Appendices_V1.2_2024-11-18.docx.txt; its exon map and PVS1 rationale were used.
• No exact c.5857G>T, p.Glu1953Ter, or p.E1953* entry was found when searched in Specifications_Table4_V1.2_2024-11-18.xlsx.txt; the governing exon 11 PTC row was present and applied.
• No exact c.5857G>T, p.Glu1953Ter, or p.E1953* entry was found when searched in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt; no splice-specific evidence from that paper was needed.

Sources

Reasoning

The variant is a genomic PTC at c.5857 in BRCA2 exon 11, with p.(Glu1953Ter). ENIGMA Specifications Table 4 gives exon 11 the pre-assigned PM5_Strong (PTC) code for a PTC where a different proven pathogenic PTC has been seen; the table's PM5_N/A exclusions are E6, E12, and E27, not E11.

Rule

ENIGMA BRCA2 Table 4 PM5 (PTC): exon 11 = PM5_Strong (PTC); apply to genomic PTC variants in eligible exons.

Evidence considered

• Case normalization identifies NM_000059.4:c.5857G>T as p.(Glu1953Ter), a genomic protein-termination-codon variant.
• The exon 11 interval in Specifications Table 4 spans c.1910 through c.6841, placing c.5857 in exon 11.
• Specifications Table 4 assigns PM5_Strong (PTC) to exon 11; its listed BRCA2 PM5_N/A exons are E6, E12, and E27, so exon 11 is eligible.
• The governing specification defines PM5_VariableWeight (PTC) as a PTC in an exon where a different proven pathogenic PTC has been seen before, used as additional weight for PVS1.

Still missing

• No direct c.5857G>T, p.Glu1953Ter, or p.E1953* row was found in Specifications_V1.2_2024-11-18.docx.txt.
• No direct c.5857G>T, p.Glu1953Ter, or p.E1953* row was found in Appendices_V1.2_2024-11-18.docx.txt.
• No direct c.5857G>T, p.Glu1953Ter, or p.E1953* row was found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt; the governing pre-assigned exon 11 PM5 row was found instead.

Sources

Reasoning

ENIGMA restricts PP4 to calibrated multifactorial likelihood evidence and specifies PP4 Supporting for LR >=2.08. The exact BRCA2 c.5857G>T row reports LR = exp(LOG(LR)) = 2.766360582136327 from 7 probands. Exact comparison: 2.766360582136327 >= 2.08? yes; PP4 Supporting is met.

Rule

ENIGMA PP4 Supporting: LR >=2.08:1.

Evidence considered

• ENIGMA states PP4 Supporting: LR >=2.08:1 and limits PP4 to combined multifactorial clinical likelihood evidence.
• The exact BRCA2 c.5857G>T row reports LOG(LR) 1.017532587051392, 7 probands, and LR 2.766360582136327.
• Exact comparison using the criterion-specific operator: 2.766360582136327 >= 2.08? yes.

Sources

Reasoning

Expert panel Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) classified as Pathogenic.

Rule

Requested rule: exact-variant ClinVar expert-panel Pathogenic/Likely pathogenic supports PP5 Supporting.

Evidence considered

• ClinVar exact-match record NM_000059.4(BRCA2):c.5857G>T (p.Glu1953Ter) is Pathogenic, reviewed by expert panel, with three stars.
• The expert-panel submitter is ENIGMA; this exact expert-panel classification, rather than laboratory submissions or the aggregate label, is the basis for PP5.
• The specification says PP5 is not used, but the requested adjudication rule explicitly requires PP5 Supporting for an exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification.
• ClinVar expert panel classification

Sources

Reasoning

ENIGMA defines BP5 Supporting with the opposite direction from PP4: LR <=0.48. The exact c.5857G>T clinical-history row reports LR 2.766360582136327. Exact comparison: 2.766360582136327 <= 0.48? no; BP5 is not met.

Rule

ENIGMA BP5 Supporting: LR <=0.48:1.

Evidence considered

• ENIGMA states BP5 Supporting: LR <=0.48:1 for combined clinical likelihood evidence against pathogenicity.
• The exact BRCA2 c.5857G>T row reports LR 2.766360582136327.
• Exact comparison using the BP5-specific operator: 2.766360582136327 <= 0.48? no.

Sources

Reasoning

The exact-variant ClinVar expert-panel record is Pathogenic, not Benign or Likely benign. Therefore the requested BP6 trigger is absent. Ordinary laboratory submissions and aggregate labels do not trigger BP6, and no exact-variant ClinVar expert-panel benign classification was identified.

Rule

Requested rule: exact-variant ClinVar expert-panel Benign/Likely benign supports BP6.

Evidence considered

• ClinVar exact-match record NM_000059.4(BRCA2):c.5857G>T (p.Glu1953Ter) is Pathogenic with expert-panel review and three stars.
• No exact-variant ClinVar expert-panel Benign or Likely benign classification was identified; ordinary laboratory submissions and aggregate labels do not trigger BP6.
• The specification says BP6 is not used, while the requested rule limits BP6 to exact-variant ClinVar expert-panel Benign/Likely benign classification; neither route supports BP6 here.

Sources

Reasoning

The ENIGMA BRCA1/2 VCEP specification reserves PS3 for well-established functional studies measuring protein function, or combined mRNA and protein effects, and directs curators to the calibrated Table 9 recommendations. The exact variant was searched in Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, HUMU-40-1557-s001.xlsx.txt, and Specifications_Table9_V1.2_2024-11-18.xlsx.txt using c.5857G>T, p.Glu1953Ter, and p.E1953*; no exact entry or calibrated PS3 assignment was found. PMID:16683254 reports the variant among deleterious changes identified in four families, but provides mutation-screening and protein-truncation-testing context rather than a validated variant-specific protein-function assay. Therefore, the available evidence is insufficient to assign PS3, and no damaging functional assay result should be inferred from the variant's truncating consequence or from generic BRCA2 functional studies.

Rule

ENIGMA BRCA2 VCEP v1.2 PS3: apply only for well-established in vitro or in vivo functional studies supportive of a damaging effect measured via protein alone or mRNA plus protein; consult calibrated Table 9 recommendations.

Evidence considered

• ENIGMA VCEP v1.2 states that PS3 functional-assay evidence must measure protein function alone or mRNA and protein together; mRNA-only evidence is handled under the alternative RNA code, not PS3.
• The governing Specifications Table 9 contains calibrated PS3/BS3 assignments for listed variants; searches for c.5857G>T, p.Glu1953Ter, and p.E1953* returned no exact entry.
• The exact-variant report in PMID:16683254 lists c.5857G4T (6085G4T), p.Glu1953X, in four families, but describes screening and protein truncation testing rather than a calibrated variant-specific protein-function result.

Still missing

• No exact variant entry was found in Specifications_Table9_V1.2_2024-11-18.xlsx.txt after searching c.5857G>T, p.Glu1953Ter, and p.E1953*.
• No exact variant entry was found in HUMU-40-1557-s001.xlsx.txt after searching c.5857G>T, p.Glu1953Ter, and p.E1953*.
• No exact variant entry was found in Appendices_V1.2_2024-11-18.docx.txt after searching c.5857G>T, p.Glu1953Ter, and p.E1953*.
• No exact variant entry was found in Specifications_V1.2_2024-11-18.docx.txt after searching c.5857G>T, p.Glu1953Ter, and p.E1953*.
• A variant-specific validated protein-function assay with calibrated PS3 strength is not available in the reviewed evidence.

Sources

Reasoning

ENIGMA requires case-control p-value <=0.05, OR >=4, and a lower confidence interval excluding 2.0. The exact variant is reported in four Dutch families and as a French-Canadian founder mutation, but no qualifying OR, p-value, or confidence interval is provided. SupplementaryTables_V1.2.xlsx was searched as the governing PS4 source but its full text is unavailable. HUMU-40-1557-s001.xlsx was searched under c.5857G>T, p.Glu1953Ter, p.E1953*, and historical notation, with no exact entry found.

Rule

ENIGMA PS4: p-value <=0.05 and OR >=4, with the lower confidence interval excluding 2.0.

Evidence considered

• ENIGMA states: Case-control studies; p-value <=0.05 and OR >=4 (lower confidence interval excludes 2.0).
• PMID:16683254 reports c.5857G4T/6085G4T, p.Glu1953X, in 4 Dutch families, but gives no qualifying PS4 case-control metrics.
• PMID:23199084 identifies c.5857G>T as a French-Canadian founder mutation and reports up to 84% for the group of listed BRCA1/2 founder mutations, not a qualifying variant-specific case-control estimate.
• SupplementaryTables_V1.2.xlsx was searched but its full text was unavailable.
• HUMU-40-1557-s001.xlsx was searched under all supplied variant notations and had no exact entry.

Still missing

• No qualifying case-control OR, p-value, or confidence interval was found for c.5857G>T.
• SupplementaryTables_V1.2.xlsx full text is unavailable, so its ST7 posterior-probability entry could not be verified.
• HUMU-40-1557-s001.xlsx was searched for c.5857G>T, p.Glu1953Ter, p.E1953*, c.5857G4T, and p.Glu1953X; no exact row was found.

Sources

Reasoning

The ENIGMA BRCA2 VCEP permits PM2 at Supporting strength only when the variant is absent from gnomAD v2.1 non-cancer exomes and gnomAD v3.1 non-cancer genomes, with regional average read depth at least 25. The case evidence instead shows the variant present in combined/all-comers gnomAD v2.1 at AF 7.96972e-06 (2/250950 alleles, zero homozygotes) and in gnomAD v4.1 at AF 2.47855e-06 (4/1613850 alleles, zero homozygotes), but does not provide the mandated non-cancer v2.1/v3.1 presence or depth data. PM2 therefore cannot be conclusively assessed under the governing VCEP rule.

Rule

ENIGMA BRCA2 VCEP PM2_Supporting: apply when absent from gnomAD v2.1 non-cancer exome-only and gnomAD v3.1 non-cancer genomes, with average regional read depth >=25; exclude failed QC data and do not apply to insertion, deletion, or delins variants.

Evidence considered

• ENIGMA BRCA2 VCEP PM2_Supporting requires absence from gnomAD v2.1 non-cancer exomes and gnomAD v3.1 non-cancer genomes, with average regional read depth at least 25 and acceptable QC.
• The case reports gnomAD v2.1 presence at 2/250950 alleles, AF 7.969715082685795e-06, and zero homozygotes.
• The case reports gnomAD v4.1 presence at 4/1613850 alleles, AF 2.4785450940298045e-06, and zero homozygotes, but v4.1 is not the VCEP-specified non-cancer source.

Still missing

• The required GNOMAD_V2_1_NON_CANCER exome and GNOMAD_V3_1_NON_CANCER genome presence/absence and regional read-depth data are not present in the case evidence.
• No variant-specific entry for c.5857G>T, p.Glu1953Ter, or p.E1953* was found in Specifications_V1.2_2024-11-18.docx.txt; its general PM2 rule was consulted.
• No variant-specific entry for c.5857G>T, p.Glu1953Ter, or p.E1953* was found in Appendices_V1.2_2024-11-18.docx.txt; its general PM2 and read-depth guidance was consulted.
• No variant-specific entry for c.5857G>T, p.Glu1953Ter, or p.E1953* was found in HUMU-40-1557-s001.xlsx.txt.

Sources

Reasoning

The ENIGMA BRCA2 VCEP specification restricts PM3 to patients with a phenotype consistent with BRCA1/2-related Fanconi anemia and a co-occurring variant in the same gene. The available case evidence does not document Fanconi-anemia clinical features or chromosome-breakage testing for a patient carrying NM_000059.4:c.5857G>T, nor does it document a second BRCA2 pathogenic/likely pathogenic variant, phase, or trans/cis relationship. Therefore, the required PM3 proband points cannot be assigned. The exact variant was not found as a PM3-specific entry in Specifications_V1.2_2024-11-18.docx; the governing rule is phenotype- and co-occurrence-based rather than a variant lookup table.

Rule

Apply PM3 only for a patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi anemia and co-occurring variants in the same gene; assign strength by ENIGMA Table 6 points.

Evidence considered

• The ENIGMA BRCA2 VCEP rule requires a patient with phenotype consistent with BRCA1/2-related Fanconi anemia plus a co-occurring same-gene variant; PM3 strength is assigned from the Table 6 point total (Supporting = 1, Moderate = 2, Strong = 4 or more).
• The case materials identify the assessed variant as NM_000059.4:c.5857G>T (p.Glu1953Ter; p.E1953*) but provide no documented Fanconi anemia phenotype, second BRCA2 pathogenic/likely pathogenic variant, or phase information for this assessment.

Still missing

• No case-level Fanconi anemia phenotype or chromosome-breakage result is documented for NM_000059.4:c.5857G>T.
• No co-occurring BRCA2 pathogenic/likely pathogenic variant or confirmed phase (trans, cis, or homozygous state) is documented.
• No PM3-specific variant entry was found when searching Specifications_V1.2_2024-11-18.docx for c.5857G>T, p.Glu1953Ter, and p.E1953*; this file supplies the governing PM3 rule rather than a variant-specific PM3 table.

Sources

Reasoning

A ClinVar criterion-lead submission reports that the BRCA2 Glu1953Ter variant segregated with disease in four affected individuals from one family and cites Phelan 1996 (PMID:8673090). However, the available record provides no pedigree, parental testing, unaffected-carrier data, meioses count, or quantitative co-segregation likelihood ratio. ENIGMA requires quantitative co-segregation analysis and assigns PP1 Supporting at LR ≥2.08, PP1_Moderate at LR ≥4.3, PP1_Strong at LR ≥18.7, and PP1_Very Strong at LR ≥350; therefore no PP1 strength can be assigned from the available evidence.

Rule

Co-segregation must be measured quantitatively: PP1 LR ≥2.08; PP1_Moderate LR ≥4.3; PP1_Strong LR ≥18.7; PP1_Very Strong LR ≥350.

Evidence considered

• A ClinVar criterion-lead signal states that the Glu1953Ter variant segregated with disease in 4 affected individuals from one family and cites Phelan 1996 (PMID:8673090).
• ENIGMA BRCA2 VCEP Specification v1.2 requires quantitative co-segregation analysis and sets PP1 thresholds at LR ≥2.08 (supporting), ≥4.3 (moderate), ≥18.7 (strong), and ≥350 (very strong).

Still missing

• Quantitative co-segregation likelihood ratio and pedigree-level meioses are unavailable.
• Parental testing, unaffected-carrier status, phenotype details, and assessment of alternative familial causes are unavailable.
• The cited Phelan 1996 source (PMID:8673090) is not present in source_registry or the case publications, so the ClinVar-reported segregation statement could not be independently verified from the primary paper.

Sources

Reasoning

The ENIGMA BRCA2 VCEP requires BA1 to use the maximum filter allele frequency in gnomAD v2.1 non-cancer exomes and/or gnomAD v3.1 non-cancer genomes, with FAF >0.001. The available case evidence contains only combined/all-comers gnomAD v2.1 and v4.1 values: total AF 7.96972e-06 and 2.47855e-06, respectively, with maximum reported subpopulation AFs of 1.7619e-05 and 3.39034e-06 and zero homozygotes. These values are below the VCEP BA1 threshold, but the mandated non-cancer v2.1/v3.1 FAF values are not available, so BA1 cannot be conclusively assessed under the governing rule.

Rule

ENIGMA BRCA2 VCEP BA1: apply when filter allele frequency is above 0.1% (FAF > 0.001) in gnomAD v2.1 non-cancer exome-only and/or gnomAD v3.1 non-cancer non-founder populations; require read depth >20 and exclude failed QC data.

Evidence considered

• ENIGMA BRCA2 VCEP BA1 requires filter allele frequency above 0.001 in gnomAD v2.1 non-cancer exomes and/or gnomAD v3.1 non-cancer genomes, using non-founder populations.
• The case reports gnomAD v2.1 total AF 7.96972e-06, maximum reported subpopulation AF 1.761897210916715e-05, and zero homozygotes; these are combined/all-comers values rather than the required non-cancer FAF.
• The case reports gnomAD v4.1 total AF 2.4785450940298045e-06, maximum reported subpopulation AF 3.3903361857361778e-06, and zero homozygotes; v4.1 is not the VCEP-specified substitute for non-cancer v2.1/v3.1 data.

Still missing

• The required GNOMAD_V2_1_NON_CANCER exome and GNOMAD_V3_1_NON_CANCER genome FAF values are not present in the case evidence.
• No variant-specific entry for c.5857G>T, p.Glu1953Ter, or p.E1953* was found in Specifications_V1.2_2024-11-18.docx.txt; its general BA1 rule was consulted.
• No variant-specific entry for c.5857G>T, p.Glu1953Ter, or p.E1953* was found in Appendices_V1.2_2024-11-18.docx.txt; its general population-frequency guidance was consulted.
• No variant-specific entry for c.5857G>T, p.Glu1953Ter, or p.E1953* was found in HUMU-40-1557-s001.xlsx.txt.

Sources

Reasoning

The ENIGMA BRCA2 VCEP requires BS1 Strong when maximum filter allele frequency is above 0.0001 and BS1 Supporting when it is above 0.00002 through 0.0001 in gnomAD v2.1 non-cancer exomes and/or gnomAD v3.1 non-cancer genomes. The available combined/all-comers gnomAD v2.1 and v4.1 values are below 0.00002, including reported maximum subpopulation AFs of 1.7619e-05 and 3.39034e-06, but the required non-cancer FAF sources are absent; therefore the VCEP BS1 rule cannot be conclusively assessed.

Rule

ENIGMA BRCA2 VCEP BS1: apply Strong for FAF >0.0001 or Supporting for FAF >0.00002 and <=0.0001 in gnomAD v2.1 non-cancer exome-only and/or gnomAD v3.1 non-cancer non-founder populations; require read depth >20 and exclude failed QC data.

Evidence considered

• ENIGMA BRCA2 VCEP assigns BS1 Strong above 0.0001 and BS1 Supporting above 0.00002 through 0.0001 using non-cancer gnomAD v2.1 exomes and/or v3.1 genomes.
• The case reports gnomAD v2.1 total AF 7.96972e-06 and maximum reported subpopulation AF 1.761897210916715e-05, with zero homozygotes.
• The case reports gnomAD v4.1 total AF 2.4785450940298045e-06 and maximum reported subpopulation AF 3.3903361857361778e-06, with zero homozygotes; these do not replace the specified non-cancer sources.

Still missing

• The required GNOMAD_V2_1_NON_CANCER exome and GNOMAD_V3_1_NON_CANCER genome FAF values are not present in the case evidence.
• No variant-specific entry for c.5857G>T, p.Glu1953Ter, or p.E1953* was found in Specifications_V1.2_2024-11-18.docx.txt; its general BS1 rule was consulted.
• No variant-specific entry for c.5857G>T, p.Glu1953Ter, or p.E1953* was found in Appendices_V1.2_2024-11-18.docx.txt; its general population-frequency guidance was consulted.
• No variant-specific entry for c.5857G>T, p.Glu1953Ter, or p.E1953* was found in HUMU-40-1557-s001.xlsx.txt.

Sources

Reasoning

The ENIGMA BRCA2 VCEP BS2 rule requires qualifying clinical or research-cohort observations of the variant in healthy adults or individuals without features of BRCA2-related Fanconi Anemia, scored by the number and age of probands; homozygotes in gnomAD are specifically excluded from BS2 scoring because frequency codes capture that evidence. The case reports zero homozygotes in gnomAD v2.1 and v4.1 but provides no qualifying phenotyped healthy-adult or Fanconi-Anemia-negative clinical observations, so BS2 cannot be assessed.

Rule

ENIGMA BRCA2 VCEP BS2: score qualifying probands without Fanconi-Anemia features; BS2 is Strong at >=4 points, Moderate at 2 points, and Supporting at 1 point. Do not apply BS2 to homozygote observations from gnomAD frequency data.

Evidence considered

• ENIGMA BRCA2 VCEP BS2 is based on scored clinical or research-cohort observations in adults without expected early-onset disease, and is applied in the absence of Fanconi-Anemia features.
• The VCEP explicitly states that homozygotes observed in gnomAD are not used for BS2 because they are already captured by BA1 or BS1 frequency codes.
• The case reports zero homozygotes in both gnomAD v2.1 and gnomAD v4.1 and provides no qualifying phenotyped healthy-adult observations.

Still missing

• No qualifying clinical or research-cohort observations with age, phenotype, phase, and Fanconi-Anemia assessment were provided.
• No variant-specific entry for c.5857G>T, p.Glu1953Ter, or p.E1953* was found in Specifications_V1.2_2024-11-18.docx.txt; its general BS2 rule was consulted.
• No variant-specific entry for c.5857G>T, p.Glu1953Ter, or p.E1953* was found in Appendices_V1.2_2024-11-18.docx.txt; its general BS2 guidance was consulted.
• No variant-specific entry for c.5857G>T, p.Glu1953Ter, or p.E1953* was found in HUMU-40-1557-s001.xlsx.txt.

Sources

Reasoning

The ENIGMA BRCA1/2 VCEP specification reserves BS3 for well-established functional studies showing no damaging effect on protein function, measured via protein alone or combined mRNA and protein, with calibrated assignments in Table 9. The exact variant was searched in Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, HUMU-40-1557-s001.xlsx.txt, and Specifications_Table9_V1.2_2024-11-18.xlsx.txt using c.5857G>T, p.Glu1953Ter, and p.E1953*; no exact entry or calibrated BS3 assignment was found. PMID:16683254 reports the variant as a deleterious change in four families but does not provide a validated assay demonstrating preserved protein function. Thus, benign functional evidence is insufficient and BS3 cannot be assigned.

Rule

ENIGMA BRCA2 VCEP v1.2 BS3: apply only for well-established in vitro or in vivo functional studies showing no damaging effect on protein function, measured via protein alone or mRNA plus protein; consult calibrated Table 9 recommendations.

Evidence considered

• ENIGMA VCEP v1.2 states that BS3 requires well-established functional evidence showing no damaging effect on protein function, measured via protein alone or mRNA plus protein.
• The governing Specifications Table 9 contains calibrated PS3/BS3 assignments for listed variants; searches for c.5857G>T, p.Glu1953Ter, and p.E1953* returned no exact entry.
• The exact-variant report in PMID:16683254 lists c.5857G4T (6085G4T), p.Glu1953X, in four families, but does not report a validated assay demonstrating retained protein function.

Still missing

• No exact variant entry was found in Specifications_Table9_V1.2_2024-11-18.xlsx.txt after searching c.5857G>T, p.Glu1953Ter, and p.E1953*.
• No exact variant entry was found in HUMU-40-1557-s001.xlsx.txt after searching c.5857G>T, p.Glu1953Ter, and p.E1953*.
• No exact variant entry was found in Appendices_V1.2_2024-11-18.docx.txt after searching c.5857G>T, p.Glu1953Ter, and p.E1953*.
• No exact variant entry was found in Specifications_V1.2_2024-11-18.docx.txt after searching c.5857G>T, p.Glu1953Ter, and p.E1953*.
• A variant-specific validated protein-function assay with calibrated BS3 strength is not available in the reviewed evidence.

Sources

Reasoning

No evidence of non-segregation, affected non-carriers, or a quantitative likelihood ratio against pathogenicity was identified for this variant. ENIGMA requires quantitative co-segregation analysis for BS4 and assigns BS4 Supporting at LR ≤0.48, BS4_Moderate at LR ≤0.23, BS4 at LR ≤0.05, and BS4_Very Strong at LR ≤0.00285; the available report of four affected segregating individuals is not evidence of lack of segregation and cannot be converted into a benign LR.

Rule

Lack of segregation must be measured quantitatively: BS4 Supporting LR ≤0.48; BS4_Moderate LR ≤0.23; BS4 LR ≤0.05; BS4_Very Strong LR ≤0.00285.

Evidence considered

• ENIGMA BRCA2 VCEP Specification v1.2 requires quantitative lack-of-segregation analysis and sets BS4 thresholds at LR ≤0.48 (supporting), ≤0.23 (moderate), ≤0.05 (strong), and ≤0.00285 (very strong).
• The available ClinVar segregation signal reports four affected segregating individuals, which is directionally inconsistent with lack of segregation but does not provide a quantitative benign-direction LR.

Still missing

• No quantitative likelihood ratio against pathogenicity or pedigree-level non-segregation analysis is available.
• SupplementaryTables_V1.2.xlsx was searched by c.5857G>T, p.Glu1953Ter, and p.E1953*, but its full text is unavailable; this is a conversion gap, not evidence absence.
• HUMU-40-1557-s001.xlsx was searched by c.5857G>T, p.Glu1953Ter, and p.E1953*; no matching entry was found.
• No unaffected carriers, affected non-carriers, parental testing, or phenotype-consistency data are available for assessing possible phenocopies or bilinearity.

Sources