Applied · 6

Strength Supporting Moderate Strong Very strong

BA1 stand-alone Benign

Met: gnomAD v2.1 non-cancer exome maximum filter allele frequency 0.00142293 exceeds the BRCA2 VCEP BA1 threshold of 0.001.

The BRCA2 VCEP specification defines BA1 as maximum filter allele frequency above 0.001 in a gnomAD non-founder population, using gnomAD v2.1 non-cancer exomes and gnomAD v3.1 non-cancer genomes with exome and genome data considered separately.The BRCA2 VCEP appendix states that BA1 was rounded to 0.001 for BRCA2 based on a minimal credible allele frequency of 0.000906, and requires filter allele frequency rather than minor allele frequency.The case evidence reports gnomAD v2.1 non-cancer exome AF 0.0002660855 from 63/236766 alleles, one homozygote, and maximum filter allele frequency 0.00142293; this exceeds 0.001.

gnomad_v2 ↗

BS1 strong Benign

Met, strong: gnomAD v2.1 non-cancer exome maximum filter allele frequency 0.00142293 exceeds the BRCA2 VCEP BS1 threshold of 0.0001.

The BRCA2 VCEP specification defines BS1 as maximum filter allele frequency above 0.0001 and BS1_Supporting as greater than 0.00002 through 0.0001 in a gnomAD non-founder population, with exome and genome data assessed separately.The BRCA2 VCEP appendix derives 0.0001 as the rounded BS1 threshold for BRCA2 and recommends the highest filter allele frequency in a non-founder population, excluding TCGA data and established pathogenic founder variants.The case evidence reports gnomAD v2.1 non-cancer exome maximum filter allele frequency 0.00142293 for this variant, exceeding the strong BS1 threshold of 0.0001.

gnomad_v2 ↗

BP1 strong review Benign

Met, Strong: synonymous Ala3246 is outside the aa 2481-3186 DNA-binding domain and SpliceAI max delta 0.013 is below the <=0.1 threshold.

ENIGMA BRCA2 v1.2 states: apply BP1_Strong for a silent substitution outside the potentially clinically important domains when no splicing is predicted (SpliceAI <=0.1).The variant is p.(Ala3246=); Ala3246 is outside the BRCA2 PALB2-binding domain aa 10-40 and DNA-binding domain aa 2481-3186.SpliceAI max delta is 0.013, which is <=0.1 and therefore satisfies the ENIGMA no-predicted-splicing condition.

spliceai ↗

BP4 supporting Benign

Met, Supporting: SpliceAI maximum delta 0.013 meets the ENIGMA BP4 threshold of <=0.1 for no predicted splice impact.

The case normalization identifies NM_000059.4:c.9738C>T as the synonymous protein change NP_000050.3:p.(Ala3246=), so the splice-impact path is applicable and REVEL is not used.The ENIGMA BRCA2 specification states that BP4 applies to a silent variant inside a potentially clinically important functional domain when SpliceAI <=0.1.The case SpliceAI result reports DS_AG 0.013, DS_AL 0.004, DS_DG 0.0, and DS_DL 0.0, with maximum delta 0.013; this meets the governing <=0.1 threshold.

spliceai ↗

BP6 supporting Benign

Met, Supporting: exact-variant ClinVar expert-panel classification is Benign for c.9738C>T (p.Ala3246=), satisfying the requested BP6 rule.

ClinVar variation 52896 exactly matches NM_000059.4(BRCA2):c.9738C>T (p.Ala3246=).The ClinVar record identifies the Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) as the expert panel and reports Benign with reviewed-by-expert-panel status.The requested exact-variant rule is satisfied: Benign expert-panel classification -> BP6 Supporting.

clinvar ↗

BP7 supporting Benign

Met, Supporting: synonymous p.Ala3246= has SpliceAI maximum delta 0.013, satisfying BP4 and the ENIGMA BP7 requirement for silent variants.

The case normalization identifies NM_000059.4:c.9738C>T as the synonymous protein change NP_000050.3:p.(Ala3246=).The ENIGMA BRCA2 specification states that BP7 Supporting applies to silent variants inside a potentially clinically important functional domain if BP4 is met, and is applied in addition to BP4.The case SpliceAI maximum delta is 0.013, which meets the ENIGMA BP4 no-impact threshold of <=0.1 and therefore satisfies the BP7 prerequisite.

spliceai ↗

Assessed · not applied · 4 not met · 8 not assessed

Pathogenic

PS3 Not assessed: no calibrated protein-function or combined mRNA-and-protein assay entry was found for c.9738C>T (p.Ala3246=).

PS4 Not met: published observations lack the ENIGMA PS4 requirements of p-value <=0.05, OR >=4, and a confidence interval excluding 2.0.

PM2 Not met: the variant is present in gnomAD v2.1 non-cancer exomes at AF 0.0002660855 and gnomAD v3.1 non-cancer genomes at AF 0.0000473491.

PM3 Not assessed: no documented Fanconi anemia phenotype, pathogenic BRCA2 co-occurring variant, phase, or PM3-scoring affected-proband observation is available.

PP1 Not assessed: no pedigree or quantitative co-segregation likelihood ratio is available to compare with the ENIGMA PP1 thresholds of 2.08, 4.3, 18.7, or 350.

PP3 Not met: SpliceAI maximum delta 0.013 is below the ENIGMA PP3 threshold of >=0.2 for predicted splicing in silent variants.

PP4 Not assessed: no exact-variant combined clinical likelihood ratio was available for comparison with the PP4 threshold of LR >=2.08.

PP5 Not met: exact-variant ClinVar expert-panel classification is Benign, not Pathogenic or Likely pathogenic, so PP5 is not triggered.

Benign

BS2 Not assessed: one gnomAD homozygote is frequency evidence, not the VCEP's required phenotyped healthy-adult observation for BS2.

BS3 Not assessed: no calibrated benign protein-function or combined mRNA-and-protein assay entry was found for c.9738C>T (p.Ala3246=).

BS4 Not assessed: no affected-relative non-segregation result or quantitative likelihood ratio is available to compare with the ENIGMA BS4 thresholds of 0.48, 0.23, 0.05, or 0.00285.

BP5 Not assessed: no exact-variant combined LR was available for comparison with the BP5 Supporting threshold of LR <=0.48.

N/A · 10 PVS1 · PS1 · PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · BP2 · BP3

Admixed American 86 / 59,994	0.14% 1 hom
Middle Eastern 1 / 6,084	0.016%
Remaining individuals 2 / 62,488	0.0032%

Admixed American 63 / 35,416	0.18% 1 hom
Remaining individuals 2 / 7,218	0.028%

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