BRCA2 c.7317A>G, p.(Gly2439=)

Reasoning

The ENIGMA BRCA1/BRCA2 CSPEC v1.2 BP1 rule states: apply BP1_Strong for a silent substitution outside a (potentially) clinically important functional domain AND no splicing predicted (SpliceAI ≤0.1). This variant, NM_000059.4:c.7317A>G / NP_000050.3:p.(Gly2439=), is a silent substitution at residue 2439. The CSPEC defines the only two (potentially) clinically important functional domains for BP1/BP7 purposes as the BRCA2 PALB2-binding domain (aa 10-40) and the BRCA2 DNA-binding domain (aa 2481-3186); residue 2439 falls outside both of these ranges (below the 2481 lower bound of the DNA-binding domain and far outside the 10-40 PALB2 domain). SpliceAI predicts no significant splice impact (max delta score = 0.012), well below the CSPEC 0.1 threshold. Both conditions of the BP1_Strong rule are therefore satisfied.

Rule

ENIGMA BRCA1/2 CSPEC v1.2 BP1_Strong: silent substitution outside clinically important functional domain (PALB2 10-40, DNA-binding 2481-3186) AND SpliceAI ≤0.1.

Evidence considered

• ENIGMA BRCA1/BRCA2 CSPEC v1.2 BP1 rule: 'Apply BP1_Strong for silent substitution, missense or in-frame insertion, deletion or delins variants outside a (potentially) clinically important functional domain AND no splicing predicted (SpliceAI ≤0.1). ... clinically important functional domains are defined as: BRCA2 PALB2 binding domain aa 10-40; BRCA2 DNA binding aa 2481-3186.'
• Variant normalizes to NP_000050.3:p.(Gly2439=), residue 2439, which lies outside both the PALB2-binding domain (aa 10-40) and the DNA-binding domain (aa 2481-3186).
• SpliceAI predicts no significant splice impact for this variant (max delta score = 0.012 / 0.01), from case prefetch/evidence data, satisfying the SpliceAI ≤0.1 requirement.

Sources

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 Benign/Likely benign classification.

Evidence considered

• ClinVar Variation ID 135813 is an exact transcript-HGVS match for NM_000059.4:c.7317A>G (p.Gly2439=).
• The exact-match audit identifies ENIGMA submission SCV000579037 as an expert-panel assertion with classification Likely benign.
• ClinVar expert panel classification

Sources

Reasoning

The ENIGMA BRCA2 v1.2 PM2 Supporting rule requires absence from controls in an outbred population in gnomAD v2.1 non-cancer exome-only and gnomAD v3.1 non-cancer, with regional average read depth >=25. This variant is observed in gnomAD v2.1 (7/251214 alleles; AF 2.786e-05) and gnomAD v4.1 (57/1613848 alleles; AF 3.532e-05), with zero homozygotes. Because the variant is present in the available qualifying gnomAD v2.1 dataset, PM2 is not met.

Rule

Absent from controls in an outbred population, from gnomAD v2.1 (non-cancer, exome only subset) and gnomAD v3.1 (non-cancer). Region around the variant must have an average read depth >=25.

Evidence considered

• ENIGMA BRCA2 v1.2 specifies PM2 Supporting for a variant absent from controls in an outbred population in gnomAD v2.1 non-cancer exome-only and gnomAD v3.1 non-cancer, with average regional read depth >=25; it also notes that a single observation is not informative.
• gnomAD v2.1 reports the variant at 7/251214 alleles (AF 2.786e-05), with zero homozygotes, so the required absence criterion is not satisfied.
• gnomAD v4.1 independently reports 57/1613848 alleles (AF 3.532e-05), with zero homozygotes.
• gnomAD-Canada v1.0 reports the variant absent, but this isolated absence cannot override its presence in the governing gnomAD v2.1 dataset.

Still missing

• The bundle does not state the local average read depth around the variant; this does not change the conclusion because the variant is observed rather than absent in gnomAD v2.1.

Sources

Reasoning

Variant is NM_000059.4:c.7317A>G, NP_000050.3:p.(Gly2439=), a synonymous substitution at codon 2439, outside both ENIGMA-catalogued (potentially) clinically important functional domains (PALB2-binding aa10-40; DNA-binding aa2481-3186). Per the ENIGMA BRCA1/2 v1.2 specification PP3 rule, PP3 can only be applied for this variant type via the splicing pathway: predicted splicing impact with SpliceAI ≥0.2 for silent variants (irrespective of domain location). SpliceAI delta scores for this variant are DS_AG=0.0, DS_AL=0.011, DS_DG=0.002, DS_DL=0.012 (max delta = 0.012), far below the 0.2 PP3 threshold, so no splice-impact evidence supports pathogenicity. The missense in-silico pathway (BayesDel no-AF ≥0.30) is not applicable because this is a synonymous change, not a missense/in-frame indel. PP3 is not met.

Rule

ENIGMA BRCA1/2 v1.2 PP3: silent variants require SpliceAI ≥0.2; observed max delta 0.012 does not meet this threshold.

Evidence considered

• SpliceAI Lookup (NM_000059.4:c.7317A>G): DS_AG=0.0, DS_AL=0.011, DS_DG=0.002, DS_DL=0.012; max delta score = 0.012; pipeline evidence_sentence: 'SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).'
• ENIGMA BRCA1/BRCA2 ACMG/AMP Specification v1.2 (Table 1, PP3 rule, cspec): PP3 applies for missense/in-frame variants inside a functional domain with BayesDel no-AF ≥0.30, OR for predicted splicing (SpliceAI ≥0.2) for silent, missense/in-frame, or intronic (outside donor/acceptor 1,2) variants.
• Variant location NP_000050.3:p.(Gly2439=) at residue 2439 falls outside both ENIGMA-defined clinically important domains (PALB2-binding aa10-40; DNA-binding aa2481-3186), making the domain-dependent missense pathway of PP3 moot for this synonymous variant regardless.
• BayesDel and REVEL scores were both queried and returned null/not found in the prefetch data; not relevant here since variant is synonymous and only the SpliceAI-based silent-variant PP3 pathway applies.

Sources

Reasoning

ClinVar exactly matches c.7317A>G/p.(Gly2439=), but its sole expert-panel submission is ENIGMA Likely benign, not Pathogenic or Likely pathogenic. Ordinary laboratory submissions were not used.

Rule

Apply PP5 only for an exact-variant ClinVar expert-panel Pathogenic/Likely pathogenic classification.

Evidence considered

• ClinVar Variation ID 135813 is an exact transcript-HGVS match for NM_000059.4:c.7317A>G (p.Gly2439=).
• The exact-match audit identifies ENIGMA submission SCV000579037 as the sole expert-panel assertion and records it as Likely benign; all other submissions are non-expert laboratory assertions.

Still missing

• An exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification would be required to meet PP5.

Sources

Reasoning

The ENIGMA BRCA2 v1.2 BA1 threshold is FAF >0.001 in a qualifying non-founder gnomAD population. The maximum reported gnomAD v2.1 non-founder population FAF is 1.687e-05 and the gnomAD v4.1 joint population FAF is 3.233e-05; both are far below 0.001. The observed allele frequency therefore does not meet BA1.

Rule

Filter allele frequency (FAF) is above 0.1% (FAF > 0.001) in gnomAD v2.1 (non-cancer, exome only subset) and/or gnomAD v3.1 (non-cancer), non-founder population(s).

Evidence considered

• ENIGMA BRCA2 v1.2 specifies BA1 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.
• gnomAD v2.1 reports grpmax FAF 1.687e-05, with 7/251214 total exome alleles and no homozygotes.
• gnomAD v4.1 reports joint grpmax FAF 3.233e-05, with 57/1613848 total alleles and no homozygotes; this is supplementary population context and does not alter the v1.2 BA1 conclusion.

Sources

Reasoning

The ENIGMA BRCA2 v1.2 BS1 Supporting threshold requires FAF >0.00002 and <=0.0001, while BS1 Strong requires FAF >0.0001, in qualifying gnomAD v2.1 and/or v3.1 populations. The qualifying gnomAD v2.1 maximum population FAF is 1.687e-05, below the Supporting lower bound, so BS1 is not met. Although gnomAD v4.1 has a maximum exome population FAF of 4.358e-05, gnomAD v4.1 is not the dataset named in this v1.2 rule and cannot be substituted for the specified v2.1/v3.1 threshold assessment.

Rule

Filter allele frequency (FAF) is above 0.002% (FAF > 0.00002) and less than or equal to 0.01% (FAF <= 0.0001) for Supporting, or above 0.01% (FAF > 0.0001) for Strong, in gnomAD v2.1 (non-cancer, exome only subset) and/or gnomAD v3.1 (non-cancer), non-founder population(s).

Evidence considered

• ENIGMA BRCA2 v1.2 specifies BS1 Supporting for FAF >0.00002 and <=0.0001, and BS1 Strong for FAF >0.0001, using gnomAD v2.1 non-cancer exome-only and/or gnomAD v3.1 non-cancer non-founder populations.
• gnomAD v2.1 reports grpmax FAF 1.687e-05, below the BS1 Supporting cutoff of >0.00002.
• gnomAD v4.1 reports joint grpmax FAF 3.233e-05 and exome grpmax FAF 4.358e-05, but v4.1 is not the population dataset specified by the governing ENIGMA v1.2 BS1 rule.

Still missing

• A qualifying gnomAD v3.1 result is not present in the case bundle; however, the available qualifying gnomAD v2.1 FAF is already below the BS1 lower threshold.

Sources

Reasoning

SpliceAI max delta score (0.012) is well below the ENIGMA ≤0.1 no-splice-impact threshold, which is consistent with a benign splicing prediction. However, the ENIGMA v1.2 BP4 rule text specifically restricts the 'silent variant, no predicted splice impact' bullet to silent variants located inside a (potentially) clinically important functional domain (BRCA2 PALB2-binding aa10-40; DNA-binding aa2481-3186); the third BP4 bullet covers only intronic variants outside donor/acceptor 1,2 sites. This variant, p.(Gly2439=), is exonic and falls outside both catalogued domains (residue 2439 precedes the 2481-3186 DNA-binding region), so it does not satisfy the literal domain-location condition of either applicable BP4 bullet. The VCEP channels this exact scenario (silent, outside domain, no splice impact) through its BP1 rule instead, which is not one of this group's assigned criteria. Because the domain-location precondition specific to BP4 is not met, BP4 is scored not_met for this variant rather than met, even though the underlying SpliceAI evidence itself is benign.

Rule

ENIGMA BRCA1/2 v1.2 BP4: silent-variant bullet requires location inside a catalogued functional domain; this variant (residue 2439) is outside both catalogued domains, so the rule's precondition is not met.

Evidence considered

• SpliceAI Lookup (NM_000059.4:c.7317A>G): max delta score = 0.012, well below the ≤0.1 no-splice-impact threshold used throughout the ENIGMA framework.
• ENIGMA BRCA1/BRCA2 ACMG/AMP Specification v1.2 (Table 1, BP4 rule, cspec): the silent-variant BP4 bullet requires the variant be inside a (potentially) clinically important functional domain (BRCA2 PALB2-binding aa10-40; DNA-binding aa2481-3186); the intronic bullet requires variant location outside donor/acceptor 1,2 sites in intronic sequence.
• Variant p.(Gly2439=) at residue 2439 is exonic (not intronic) and lies outside both ENIGMA-catalogued domains, so neither applicable BP4 bullet's domain/location precondition is satisfied by this variant despite the benign SpliceAI score.

Sources

Reasoning

The ENIGMA v1.2 BP7 supporting-strength rule applies to (a) silent variants inside a catalogued functional domain, if BP4 is met, or (b) intronic variants beyond the conserved donor/acceptor motif positions (+7/-21), if BP4 is met. This variant, p.(Gly2439=), is exonic and outside both catalogued domains, so neither bullet's location condition applies, and BP4 was not scored met for this variant under this group's assessment (see BP4 rationale). The BP7_Strong(RNA) rule requires well-established functional mRNA-transcript studies showing no damaging effect; no such functional/mRNA assay data for this variant were found in the case bundle. No paper_extracts entries or full-text sources in this bundle report variant-specific splicing/transcript data for c.7317A>G. BP7 is therefore not met based on currently available evidence.

Rule

ENIGMA BRCA1/2 v1.2 BP7: supporting-strength requires domain location (not met here) or specific intronic position (not applicable, variant is exonic) combined with BP4 met; Strong(RNA) requires functional mRNA data (not available).

Evidence considered

• SpliceAI Lookup (NM_000059.4:c.7317A>G): max delta score = 0.012.
• ENIGMA BRCA1/BRCA2 ACMG/AMP Specification v1.2 (Table 1, BP7 rule, cspec): supporting-strength BP7 requires either a silent variant inside a catalogued functional domain with BP4 met, or an intronic variant beyond +7/-21 with BP4 met; BP7_Strong(RNA) requires well-established functional mRNA-transcript studies of no damaging effect.
• Variant p.(Gly2439=) is exonic and outside both ENIGMA-catalogued functional domains, so the domain-dependent BP7 supporting bullet does not apply, and no functional mRNA assay data for this variant were identified in the case bundle to support BP7_Strong(RNA).

Still missing

• No mRNA/minigene splicing assay data identified for NM_000059.4:c.7317A>G in the case bundle; if such functional transcript data become available they could support BP7_Strong(RNA) evaluation.
• The Houdayer et al. 2012 (PMID:22505045) VCEP-supplied splice-prediction benchmarking paper is referenced as supporting material for PP3/BP4/BP7 in this gene's VCEP file index, but no case-specific extraction of that paper is present in paper_extracts.json and no evidence was found indicating it discusses this specific variant.

Sources

Reasoning

ENIGMA BRCA2 v1.2 cspec PS3 requires well-established in vitro/in vivo functional studies (protein-only or mRNA+protein combined assays) showing a damaging effect, with strength assigned per Specifications Table 9 calibrated assay results. NM_000059.4:c.7317A>G / NP_000050.3:p.(Gly2439=) is a synonymous (silent) exonic substitution. The VCEP curated functional-assay table (Specifications_Table9_V1.2) extracted in this case bundle contains only 26 rows from an interim Dace & Findlay saturation genome editing dataset spanning positions c.213-c.301+2 (an unrelated early-exon region), and does not include c.7317A>G. The BRCA1/BRCA2 multifactorial dataset (HUMU-40-1557-s001 SuppT1/SuppT4, Parsons et al. 2019) sample rows extracted in this bundle likewise do not include c.7317A>G, and no gene-cache or full-text search located a mammalian functional assay (minigene, SGE, HDR, or splicing-reporter) result for this specific variant. No qualifying functional-assay evidence was located.

Rule

ENIGMA BRCA1/BRCA2 v1.2 PS3 (Specifications_V1.2_2024-11-18.docx Table 1; Appendix E; Specifications Table 9)

Still missing

• No variant-specific functional assay (protein, mRNA/splicing, or combined) result for NM_000059.4:c.7317A>G was located in the VCEP Specifications Table 9 calibrated assay table, the HUMU-40-1557-s001 multifactorial supplementary tables, or any full-text/paper_extracts source in this case bundle.
• If a full lookup of Specifications Table 9 / HUMU-40-1557-s001 by exact HGVS c.7317A>G has not yet been performed beyond the truncated excerpts captured in vcep_materials.json, that direct lookup should be completed before finalizing PS3 as not_assessed.

Reasoning

No exact-variant case-control enrichment study or ENIGMA case-control likelihood ratio was identified. The available literature extractions do not report c.7317A>G/p.(Gly2439=), and the ClinVar-linked Spanish cohort reports a different synonymous BRCA2 variant (c.7545A>G), not the queried variant.

Rule

ENIGMA BRCA2 v1.2 PS4: case-control p<=0.05 and OR>=4 with lower confidence interval excluding 2.0.

Evidence considered

• ENIGMA BRCA2 v1.2 requires significantly increased prevalence in affected individuals versus controls, with p<=0.05, OR>=4, and lower confidence interval excluding 2.0, for PS4 at Strong strength.
• The ENIGMA multifactorial dataset was checked for the exact queried HGVS/protein designation; no matching c.7317A>G or p.(Gly2439=) record was supplied.
• The precomputed extraction for PMID:21918853 confirms that its reported synonymous BRCA2 observation is c.7545A>G/p.Glu2439Glu rather than the queried c.7317A>G/p.(Gly2439=); it therefore cannot supply PS4 evidence.

Still missing

• A case-control dataset with exact c.7317A>G carrier counts, control counts, odds ratio, confidence interval, and p-value.
• Alternatively, an exact-variant ENIGMA multifactorial/case-control likelihood-ratio record.

Sources

Reasoning

The applicable ClinGen ENIGMA BRCA2 specification limits PM3 to a patient with a phenotype consistent with BRCA1- or BRCA2-related Fanconi anemia and co-occurring variants in the same gene, with strength assigned from phenotype and proband-specific PM3 points. The case bundle provides no affected-proband report, Fanconi-anemia phenotype or chromosome-breakage result, second BRCA2 variant, phase, or inheritance information for NM_000059.4:c.7317A>G. PM3 therefore cannot be assessed.

Rule

ENIGMA BRCA2 V1.2 PM3: apply for a patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi anemia and co-occurring variants in the same gene; assign PM3 strength from the summed PM3-related points per proband (Supporting = 1 point, Moderate = 2 points, Strong = at least 4 points).

Evidence considered

• The ENIGMA BRCA2 specification states that PM3 requires a patient with a phenotype consistent with BRCA1- or BRCA2-related Fanconi anemia and co-occurring variants in the same gene; it assigns Supporting, Moderate, or Strong weight using PM3-related points per proband.
• Review of the consolidated case-evidence bundle found no documented second BRCA2 variant, affected-proband Fanconi-anemia phenotype, chromosome-breakage result, phase, or inheritance observation for this variant.

Still missing

• Affected-proband clinical phenotype consistent with BRCA1/2-related Fanconi anemia is not provided.
• Chromosome-breakage testing result is not provided.
• No co-occurring pathogenic or likely pathogenic BRCA2 variant is documented.
• Phase and inheritance of any second variant are not documented.
• The proband-level observations needed to calculate ENIGMA PM3 points are unavailable.

Sources

Reasoning

The ENIGMA BRCA2 specification permits PP1 only for quantitative co-segregation with disease in multiple affected family members, with Supporting at LR >=2.08, Moderate at LR >=4.3, Strong at LR >=18.7, and Very Strong at LR >=350. The case bundle contains no proband pedigree, affected-relative genotypes and phenotypes, meioses, segregation likelihood ratio, or other quantitative co-segregation result; therefore PP1 cannot be assigned.

Rule

Quantitative co-segregation with disease in multiple affected family members; PP1 Supporting LR >=2.08, PP1 Moderate LR >=4.3, PP1 Strong LR >=18.7, and PP1 Very Strong LR >=350.

Evidence considered

• ENIGMA BRCA1/2 VCEP specification v1.2 requires quantitative co-segregation in multiple affected family members and sets PP1 thresholds of LR >=2.08 for Supporting, >=4.3 for Moderate, >=18.7 for Strong, and >=350 for Very Strong.
• The case-evidence bundle provides no case-specific segregation, family, parental-testing, meiosis, or quantitative LR observation for NM_000059.4:c.7317A>G.

Still missing

• Case-level pedigree and affected-relative phenotype data are missing.
• Variant testing results for affected and unaffected relatives are missing.
• Number of informative meioses and a quantitative co-segregation likelihood ratio are missing.

Sources

Reasoning

No exact-variant ENIGMA multifactorial clinical-history likelihood ratio was identified. Breast cancer phenotype alone is insufficient because ENIGMA limits PP4 to quantitative combined likelihood evidence.

Rule

ENIGMA BRCA2 v1.2 PP4: use only quantitative multifactorial clinical evidence toward pathogenicity; Supporting LR>=2.08, Moderate>=4.3, Strong>=18.7, Very Strong>=350.

Evidence considered

• ENIGMA BRCA2 v1.2 permits PP4 only for a combined multifactorial clinical LR toward pathogenicity: Supporting >=2.08, Moderate >=4.3, Strong >=18.7, or Very Strong >=350.
• The supplied BRCA2 clinical-history LR material was checked for exact Gene=BRCA2 and HGVS_Nucleotide=c.7317A>G; no matching LR was supplied.

Still missing

• An exact BRCA2 c.7317A>G clinical-history or combined multifactorial LR meeting an ENIGMA PP4 threshold.

Sources

Reasoning

The ENIGMA BRCA2 v1.2 BS2 rule requires the Specifications Table 8 point-based assessment, with points assigned per proband and consideration of the specified Fanconi Anemia stipulations. The bundle provides aggregate gnomAD observations and reports no homozygotes, but it does not provide identifiable healthy adult probands, co-occurring pathogenic variants, or the Table 8 variables needed to assign BS2 points. Aggregate absence of homozygotes alone is not sufficient to apply this BRCA2-specific BS2 rule.

Rule

Applied in absence of features of recessive disease, namely Fanconi Anemia phenotype. See Specifications Table 8 for additional stipulations, and approach to assign points per proband, and final BS2 code assignment based on the sum of BS2-related points.

Evidence considered

• ENIGMA BRCA2 v1.2 states that BS2 is applied using Specifications Table 8, with final code strength based on the sum of BS2-related points; the Strong threshold is >=4 points, Moderate is 2 points, and Supporting is 1 point.
• The gnomAD v2.1 and v4.1 aggregate records each report zero homozygotes, but they do not identify individual healthy adult probands or provide the Table 8 clinical and phase stipulations needed for BS2 scoring.

Still missing

• Specifications Table 8 point-level data for identifiable variant-positive individuals are not available in the case bundle.
• No case-level evidence establishes healthy-adult status, phase, co-occurring pathogenic BRCA2 variants, or absence of Fanconi Anemia features for BS2 scoring.

Sources

Reasoning

ENIGMA BRCA2 v1.2 cspec BS3 requires well-established in vitro/in vivo functional studies (protein-only or mRNA+protein combined assays) showing no damaging effect, with strength/code recommendations drawn from Specifications Table 9 calibrated assay results. As with PS3, no variant-specific functional assay result for NM_000059.4:c.7317A>G / NP_000050.3:p.(Gly2439=) was located in the VCEP curated functional-assay table excerpts, the multifactorial supplementary tables, or literature full-text extracted in this case bundle. ClinVar classifies this variant Likely benign with ENIGMA expert-panel concurrence (evaluated separately under PP5/BP6), but that clinical classification cannot be used to infer a functional-assay-based BS3 call per instructions to never infer a criterion from another source's final classification.

Rule

ENIGMA BRCA1/BRCA2 v1.2 BS3 (Specifications_V1.2_2024-11-18.docx Table 1; Appendix E; Specifications Table 9)

Still missing

• No variant-specific functional assay (protein, mRNA/splicing, or combined) result for NM_000059.4:c.7317A>G was located in the VCEP Specifications Table 9 calibrated assay table, the HUMU-40-1557-s001 multifactorial supplementary tables, or any full-text/paper_extracts source in this case bundle.
• If a direct row-level lookup of Specifications Table 9 / HUMU-40-1557-s001 by exact HGVS c.7317A>G (beyond the truncated excerpts captured in vcep_materials.json) has not yet been performed, that lookup should be completed before finalizing BS3 as not_assessed.

Reasoning

The ENIGMA BRCA2 specification permits BS4 only for quantitatively demonstrated lack of segregation in affected family members. The case bundle contains no affected-relative testing, non-segregation observation, informative meioses, or quantitative likelihood ratio; therefore BS4 cannot be assigned at Supporting, Moderate, Strong, or Very Strong strength.

Rule

Quantitative lack of segregation in affected family members; BS4 Supporting LR <=0.48, BS4 Moderate LR <=0.23, BS4 Strong LR <=0.05, and BS4 Very Strong LR <=0.00285.

Evidence considered

• ENIGMA BRCA1/2 VCEP specification v1.2 requires a quantitative lack-of-segregation analysis and sets BS4 thresholds of LR <=0.48 for Supporting, <=0.23 for Moderate, <=0.05 for Strong, and <=0.00285 for Very Strong.
• The case-evidence bundle provides no case-specific non-segregation, family, parental-testing, meiosis, or quantitative LR observation for NM_000059.4:c.7317A>G.

Still missing

• Case-level pedigree and affected-relative phenotype data are missing.
• Variant testing results for affected relatives are missing, including any non-segregating affected individuals.
• Number of informative meioses and a quantitative non-segregation likelihood ratio are missing.

Sources

Reasoning

No exact-variant ENIGMA multifactorial clinical-history likelihood ratio against pathogenicity was identified. Co-observation with another breast/ovarian cancer risk-gene variant is explicitly not an alternative basis for BP5 in the ENIGMA specification.

Rule

ENIGMA BRCA2 v1.2 BP5: use only quantitative multifactorial clinical evidence against pathogenicity; Supporting LR<=0.48, Moderate<=0.23, Strong<=0.05, Very Strong<=0.00285; do not use co-observation as an alternative basis.

Evidence considered

• ENIGMA BRCA2 v1.2 permits BP5 only for a combined multifactorial clinical LR against pathogenicity: Supporting <=0.48, Moderate <=0.23, Strong <=0.05, or Very Strong <=0.00285.
• The supplied BRCA2 clinical-history LR material was checked for exact Gene=BRCA2 and HGVS_Nucleotide=c.7317A>G; no matching LR was supplied.

Still missing

• An exact BRCA2 c.7317A>G clinical-history or combined multifactorial LR meeting an ENIGMA BP5 threshold.

Sources