Variant classification summary

NM_000059.3:c.3881T>G

BRCA2 · NP_000050.2:p.(Leu1294Ter) · NM_000059.3

GRCh37: chr13:32912373 T>G · GRCh38: chr13:32338236 T>G

Gene: BRCA2 Transcript: NM_000059.3

Final call

Pathogenic

PVS1 very strong PM5 strong PM2 supporting PP5 supporting

Variant details

Gene

BRCA2

Transcript

NM_000059.3

Protein

NP_000050.2:p.(Leu1294Ter)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000059.3:c.3881T>G (p.Leu1294Ter) is a nonsense variant in BRCA2 exon 11 that introduces a premature termination codon at residue 1294 of 3418, predicted to result in loss of the C-terminal DNA-binding domain and nuclear localization signals.

2

PVS1 (Very Strong) is met per ENIGMA Specifications Table 4, which assigns PVS1 to BRCA2 exon 11 PTC variants. Loss of function is the established disease mechanism for BRCA2.

3

PM5_Strong (PTC) is met per ENIGMA Table 4, which assigns PM5_Strong (PTC) for BRCA2 exon 11 termination codon variants. Exon 11 harbors numerous proven pathogenic PTC variants.

4

PM2_Supporting is met: the variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, consistent with a rare pathogenic variant in outbred populations.

5

The variant has been classified as Pathogenic by the ENIGMA expert panel and 7 clinical laboratories in ClinVar (VariationID: 266780).

6

Under ENIGMA Table 3 combining rules, PVS1 (Very Strong) + PM5_Strong + PM2_Supporting meets the criteria for Pathogenic classification (1 Very Strong + 1 Strong fulfills the Pathogenic threshold).

Final determination: ENIGMA Table 3: 1 Very Strong criterion (PVS1) plus 1 Strong criterion (PM5) meets the Pathogenic threshold; independently, 1 Very Strong plus 2 Supporting (PM2 + PP5) also meets the Pathogenic threshold.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	Met	Nonsense variant NM_000059.3:c.3881T>G (p.Leu1294Ter) in BRCA2 exon 11 introduces a premature termination codon predicted to truncate the protein at residue 1294 of 3418, removing the C-terminal DNA-binding domain (aa 2481-3186) and nuclear localization signals. Loss of function is the established disease mechanism for BRCA2. Per ENIGMA Specifications Table 4, BRCA2 exon 11 PTC variants are assigned PVS1 (Very Strong). No predicted or observed rescue via alternative splicing (SpliceAI max delta = 0.00).	vcep_specifications_table4_v1_2_2024_11_18 cspec spliceai pvs1_gene_context
PM5	Met	Per ENIGMA Specifications Table 4, BRCA2 exon 11 PTC variants are assigned PM5_Strong (PTC). Exon 11 is not among the PM5_N/A exons (E12, E27, E6), and numerous proven pathogenic PTC variants have been reported in this exon. This provides additional weight beyond PVS1 for the protein termination codon.	vcep_specifications_table4_v1_2_2024_11_18 cspec pm5_candidates
PM2	Met	Variant is absent from gnomAD v2.1 (exome), gnomAD v4.1, and gnomAD-Canada v1.0. Per ENIGMA PM2 rule, absence from controls in outbred populations supports PM2_Supporting. gnomAD v2.1/v4.1 returned null allele counts consistent with absence from the database. gnomAD-Canada confirms zero allele observations.	gnomad_v2 gnomad_v4 gnomad_canada cspec
BA1	Not met	Variant is absent from gnomAD. ENIGMA BA1 requires filter allele frequency (FAF) above 0.1% (FAF > 0.001) in gnomAD non-founder populations. The variant does not meet this threshold.	gnomad_v2 gnomad_v4 gnomad_canada cspec
BS1	Not met	Variant is absent from gnomAD. ENIGMA BS1 requires FAF above 0.002% (BS1_Supporting) or above 0.01% (BS1). The variant does not meet either threshold.	gnomad_v2 gnomad_v4 gnomad_canada cspec
PM1	N/A	PM1 is not applicable under ENIGMA BRCA2 VCEP v1.2. Per CSPEC rules, PM1 is considered a component of bioinformatic analysis (PP3/BP4) rather than an independent criterion.	cspec
PP5	Met	Expert panel Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) classified as Pathogenic.	cspec clinvar
PS1	N/A	PS1 under ENIGMA applies to missense substitutions with a previously classified pathogenic variant at the same residue, or to exonic/intronic variants with the same predicted splicing impact as a known pathogenic variant. This variant is a nonsense (PTC) change, not a missense substitution, and SpliceAI shows no splicing impact (max delta = 0.00). PS1 rules do not apply.	cspec spliceai
PS2	N/A	ENIGMA BRCA2 VCEP v1.2 marks PS2 as not applicable.	cspec
PS3	Not assessed	No variant-specific functional assay data available for NM_000059.3:c.3881T>G. ENIGMA Specifications Table 9 (calibrated functional assay results) does not list this variant. Five full-text papers were reviewed (PMID:10570174, PMID:22193408, PMID:24312913, PMID:20104584, PMID:25741868) and none reported functional data for this specific variant. OncoKB classifies the variant as 'Likely Oncogenic' with a 'Likely Loss-of-function' biological effect based on curated literature, but this is a somatic annotation and does not constitute calibrated germline PS3 evidence.	vcep_specifications_table9_v1_2_2024_11_18 oncokb
PS4	Not assessed	No case-control study data with odds ratios available for this specific variant. ENIGMA PS4 requires case-control studies with p ≤ 0.05 and OR ≥ 4 (lower CI excludes 2.0). The variant has been reported in ClinVar as Pathogenic by 7 clinical laboratories and by the ENIGMA expert panel, suggesting it has been observed in affected individuals, but quantitative case-control data are not available for formal PS4 application.	clinvar
PS5	N/A	PS5 is not included in the assess list for this adjudication.
PM6	N/A	ENIGMA BRCA2 VCEP v1.2 marks PM6 as not applicable.	cspec
PP1	Not assessed	No cosegregation data available for this variant. ENIGMA PP1 requires quantitative cosegregation analysis with LR ≥ 2.08 (Supporting), ≥ 4.3 (Moderate), or ≥ 18.7 (Strong). No cosegregation LR data were found in the reviewed evidence sources.	cspec
PP2	N/A	ENIGMA BRCA2 VCEP v1.2 marks PP2 as not applicable.	cspec
PP3	Not met	ENIGMA PP3 applies to: (a) missense/in-frame variants inside a clinically important functional domain with BayesDel no-AF score ≥ 0.30, or (b) variants with predicted splicing impact (SpliceAI ≥ 0.2). This variant is a nonsense change, not a missense. SpliceAI max delta score is 0.00, indicating no predicted splicing impact. Neither condition for PP3 is met.	cspec spliceai bayesdel
PP4	Not assessed	No clinical history likelihood ratio data available for this variant. ENIGMA PP4 requires combined LR ≥ 2.08 (Supporting), ≥ 4.3 (Moderate), or ≥ 18.7 (Strong) from multifactorial likelihood clinical data. The variant was not found in the Li et al. 2020 (PMID:31853058) BRCA2 clinical history LR table. The variant was not found in the Parsons et al. 2019 (HUMU-40-1557-s001) multifactorial analysis table (which primarily covers missense and splicing variants).	vcep_pmid_31853058_brca2_clinical_history_lr vcep_humu_40_1557_s001
BS2	Not assessed	No proband-level data with Fanconi anemia phenotype assessment available. ENIGMA BS2 requires evaluation of probands for absence of recessive Fanconi Anemia features, with point-based assignment per Specifications Table 8. No individual-level clinical data were available for review.	cspec
BS3	Not assessed	No variant-specific functional assay data showing no damaging effect. ENIGMA Specifications Table 9 (calibrated functional assay results for PS3/BS3) does not list this variant. Five full-text papers were reviewed (PMID:10570174, PMID:22193408, PMID:24312913, PMID:20104584, PMID:25741868) and none reported benign functional data for this specific variant.	vcep_specifications_table9_v1_2_2024_11_18
BS4	Not assessed	No cosegregation data available. ENIGMA BS4 requires quantitative lack-of-segregation analysis with LR ≤ 0.48 (Supporting), ≤ 0.23 (Moderate), or ≤ 0.05 (Strong). No segregation LR data were found for this variant.	cspec
BP1	N/A	ENIGMA BP1 applies to silent, missense, or in-frame insertion/deletion/delins variants outside a clinically important functional domain with no splicing predicted. This variant is a nonsense change and does not fall within the scope of BP1.	cspec
BP2	N/A	ENIGMA BRCA2 VCEP v1.2 marks BP2 as not applicable.	cspec
BP3	N/A	Trivially not applicable — in-frame deletions/insertions in repetitive regions without known function. This is a single-nucleotide nonsense substitution.
BP4	N/A	ENIGMA BP4 applies to missense/in-frame variants inside a clinically important functional domain with no predicted impact (BayesDel ≤ 0.18 AND SpliceAI ≤ 0.1), or to silent/intronic variants with no splicing impact. This variant is a nonsense change and is not eligible for BP4 under ENIGMA rules.	cspec
BP5	Not assessed	No multifactorial likelihood data supporting benignity available for this variant. ENIGMA BP5 requires combined LR ≤ 0.48 (Supporting), ≤ 0.23 (Moderate), or ≤ 0.05 (Strong). The variant was not found in the Li et al. 2020 (PMID:31853058) BRCA2 clinical history LR table or the Parsons et al. 2019 multifactorial analysis.	vcep_pmid_31853058_brca2_clinical_history_lr vcep_humu_40_1557_s001
BP6	N/A	ENIGMA BRCA2 VCEP v1.2 marks BP6 as not applicable.	cspec
BP7	N/A	ENIGMA BP7 applies to silent/intronic/missense variants with mRNA assay evidence of no splicing impact, or to silent variants inside clinically important domains if BP4 is met. This variant is a nonsense change and is not eligible for BP7.	cspec

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