Variant classification summary

NM_000059.4:c.10027G>T

BRCA2 · NP_000050.3:p.(Glu3343Ter) · NM_000059.4

GRCh37: chr13:32972677 G>T · GRCh38: chr13:32398540 G>T

Gene: BRCA2 Transcript: NM_000059.4

Final call

VUS

PM2 supporting

Variant details

Gene

BRCA2

Transcript

NM_000059.4

Protein

NP_000050.3:p.(Glu3343Ter)

gnomAD AF

ClinVar

Likely benign

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000059.4:c.10027G>T (p.Glu3343Ter) is a nonsense variant in BRCA2 exon 27 that introduces a premature termination codon at position 3343 of 3418 amino acids.

2

PVS1 is not applicable per ENIGMA BRCA2 Table 4: nonsense variants in exon 27 beyond codon p.E3309 are assigned PVS1_N/A, as truncation of the extreme C-terminus is not considered sufficient evidence for pathogenicity under the ENIGMA decision framework.

3

PM2_Supporting is met: the variant is absent from gnomAD v2.1 (non-cancer, exome), gnomAD v4.1 (non-cancer), and gnomAD-Canada v1.0 outbred populations.

4

PP3 is not met: although BayesDel no-AF score is 0.65 (≥0.30), the variant lies at position 3343, outside the BRCA2 clinically important functional domains (DNA binding domain aa 2481-3186; PALB2 binding domain aa 10-40). SpliceAI max delta is 0.17 (<0.20 threshold).

5

BA1 and BS1 are not met: the variant is absent from gnomAD; filter allele frequency does not exceed benign population thresholds.

6

PS3 and BS3 are not assessed: no variant-specific functional assay data were identified in ENIGMA Table 9 or in any of the six reviewed publications.

7

PP4 and BP5 are not assessed: the variant was not present in the Li et al. 2020 (PMID:31853058) BRCA2 clinical-history likelihood-ratio table; no multifactorial likelihood data are available.

8

ClinVar reports this variant as Likely benign (1 clinical laboratory, criteria provided, single submitter; variation ID 1770751). PP5 is not applicable under ENIGMA specifications, and no expert panel classification exists to warrant an override.

9

With only PM2_Supporting met and PVS1 not applicable per ENIGMA Table 4, the available evidence is insufficient to classify this variant as pathogenic or likely pathogenic. Multiple evidence categories (functional, segregation, clinical history, case-control) lack data. The variant remains a variant of uncertain significance (VUS).

Final determination: A single pathogenic Supporting criterion (PM2) with zero benign criteria does not meet any ENIGMA Table 3 combination rule for a classified outcome, and the point total of +1 falls within the Uncertain Significance range (-1 to 5).

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	N/A	Per ENIGMA BRCA2 Table 4, nonsense (PTC) variants in exon 27 at codon position > p.E3309 are assigned PVS1_N/A. This variant produces p.Glu3343Ter, which lies beyond the PVS1-applicable C-terminal boundary. Truncation of the extreme C-terminus (last ~75 residues) is not considered sufficient for PVS1 under ENIGMA specifications.	vcep_specifications_table4_v1_2_2024_11_18
PS1	N/A	PS1 applies to predicted missense substitutions or variants with same predicted splicing impact as a classified pathogenic variant. This is a nonsense (PTC) variant, not a missense change, and has no same-residue pathogenic missense comparator.
PS2	N/A	PS2 is not applicable under ENIGMA BRCA2 specifications.	cspec
PS3	Not assessed	No variant-specific functional assay data found in ENIGMA Table 9 for c.10027G>T. The variant was not identified in any publication. OncoKB labels it 'Likely Oncogenic' based on inferred loss-of-function from truncation, but this is a computational inference rather than direct experimental evidence and cannot substitute for calibrated functional assay data under ENIGMA PS3 rules.	vcep_specifications_table9_v1_2_2024_11_18 oncokb
PS4	Not assessed	No case-control data available for this variant. The variant is absent from gnomAD and has not been reported in any case-control study. ENIGMA PS4 requires p≤0.05 and OR≥4 with lower CI excluding 2.0, for which no data exist.	gnomad_v2 gnomad_v4
PS5	Not met	PS5 requires a reputable source to have recently reported the variant as pathogenic. The only ClinVar submission for this variant classifies it as Likely benign (1 clinical laboratory, review status: criteria provided, single submitter). No source reports this variant as pathogenic.	clinvar
PM1	N/A	PM1 is not applicable under ENIGMA BRCA2 specifications.	cspec
PM2	Met	This variant is absent from gnomAD v2.1 (non-cancer, exome) and gnomAD v4.1 (non-cancer) outbred populations. Per ENIGMA PM2 rule, absence from controls in outbred populations qualifies for PM2_Supporting. Read depth at the variant region has not been independently verified but BRCA2 exon 27 is well-covered in exome sequencing.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	Per ENIGMA BRCA2 Table 4, exon 27 PTC variants at codon position > p.E3309 are assigned PM5_N/A. This variant produces p.Glu3343Ter, beyond the PM5_PTC boundary.	vcep_specifications_table4_v1_2_2024_11_18
PM6	N/A	PM6 is not applicable under ENIGMA BRCA2 specifications.	cspec
PP1	Not assessed	No co-segregation data available for this variant. ENIGMA PP1 requires quantitative co-segregation analysis with LR ≥ 2.08:1 for Supporting, ≥ 4.3:1 for Moderate, or ≥ 18.7:1 for Strong.
PP2	N/A	PP2 is not applicable under ENIGMA BRCA2 specifications.	cspec
PP3	Not met	Per ENIGMA PP3 rules: (a) For protein change impact, requires BayesDel no-AF score ≥ 0.30 AND location inside a clinically important functional domain (BRCA2 DNA binding domain aa 2481-3186 or PALB2 binding domain aa 10-40). BayesDel score is 0.65 (≥0.30 threshold met), but the variant is at position 3343, outside both functional domains. (b) For splicing impact, requires SpliceAI ≥ 0.20. SpliceAI max delta score is 0.17, below threshold. Neither PP3 pathway is satisfied.	bayesdel spliceai
PP4	Not assessed	The variant was not found in the Li et al. 2020 (PMID:31853058) BRCA2 clinical-history likelihood-ratio spreadsheet. No multifactorial likelihood data supporting pathogenicity are available. ENIGMA PP4 requires clinical-history LR ≥ 2.08:1 for Supporting.	vcep_pmid_31853058_brca2_clinical_history_lr
PP5	N/A	PP5 is not applicable under ENIGMA BRCA2 specifications. The ClinVar submission is Likely benign from a single clinical laboratory, not an expert panel classification that would warrant a PP5 override.	cspec clinvar
BA1	Not met	Per ENIGMA BA1, filter allele frequency must be above 0.1% (FAF > 0.001) in gnomAD non-founder populations. The variant is absent from gnomAD v2.1 and v4.1; FAF is effectively 0.	gnomad_v2 gnomad_v4
BS1	Not met	Per ENIGMA BS1, BS1_Strong requires FAF > 0.0001 and BS1_Supporting requires FAF > 0.00002 in gnomAD non-founder populations. The variant is absent from gnomAD; neither threshold is met.	gnomad_v2 gnomad_v4
BS2	Not assessed	No data on observation of this variant in healthy adults without features of Fanconi Anemia. ENIGMA BS2 requires proband-level data with point assignment per Specifications Table 8. No such data are available.
BS3	Not assessed	No variant-specific functional assay data showing no damaging effect were found in ENIGMA Table 9 or in any publication. The variant is not listed in the curated functional assay results.	vcep_specifications_table9_v1_2_2024_11_18
BS4	Not assessed	No segregation data available for this variant. ENIGMA BS4 requires quantitative co-segregation analysis with LR ≤ 0.48:1 for Supporting, ≤ 0.23:1 for Moderate, or ≤ 0.05:1 for Strong.
BP1	N/A	BP1 applies to missense, silent, or in-frame variants outside clinically important functional domains with no splicing predicted. This is a nonsense (PTC) variant; BP1 is not designed for nonsense variants under the ENIGMA bioinformatic code flowchart (Figure 1A).
BP2	N/A	BP2 is not applicable under ENIGMA BRCA2 specifications.	cspec
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions; not applicable to this nonsense substitution variant.
PM3	N/A	PM3 applies to recessive disorders with a pathogenic variant in trans; trivially not applicable for this heterozygous BRCA2 variant assessment without Fanconi Anemia phenotype data.
PM4	N/A	PM4 applies to in-frame deletions/insertions or stop-loss variants; this is a nonsense substitution and PM4 is not applicable per ENIGMA specifications.
BP4	N/A	BP4 applies to missense, in-frame, silent, or intronic variants per the ENIGMA bioinformatic code flowchart (Figure 1A). Nonsense (PTC) variants do not enter this flowchart; BP4 is not designed for PTC variants.
BP5	Not assessed	The variant was not found in the Li et al. 2020 (PMID:31853058) BRCA2 clinical-history likelihood-ratio spreadsheet. No multifactorial likelihood data supporting benignity are available. ENIGMA BP5 requires clinical-history LR ≤ 0.48:1 for Supporting.	vcep_pmid_31853058_brca2_clinical_history_lr
BP6	N/A	BP6 is not applicable under ENIGMA BRCA2 specifications.	cspec
BP7	N/A	BP7 applies to silent and intronic variants with no predicted splicing impact, or to variants with well-established mRNA assay data showing no damaging effect. This is a nonsense (PTC) variant; BP7 is not designed for PTC variants. No mRNA assay data are available.

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