LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-10-02
Case ID: NM_000059.4_c.5857G_T_20261002_012329
Framework: ACMG/AMP 2015 with ENIGMA Table 3 adaptations
Variant classification summary

NM_000059.4:c.5857G>T

BRCA2  · NP_000050.3:p.(Glu1953Ter)  · NM_000059.4
GRCh37: chr13:32914349 G>T  ·  GRCh38: chr13:32340212 G>T
Gene: BRCA2 Transcript: NM_000059.4
Final call
Pathogenic
PVS1 very strong PM5 strong PP4 supporting PP5 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
BRCA2
Transcript
NM_000059.4
Protein
NP_000050.3:p.(Glu1953Ter)
gnomAD AF
2.4785450940298045e-06 (v4.1)
ClinVar
Pathogenic
OncoKB
Likely Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
Pathogenic: PVS1 (very strong) applies to the exon 11 nonsense variant p.Glu1953Ter under ENIGMA Table 4.
2
Pathogenic: PM5 (strong) is pre-assigned by ENIGMA Table 4 for BRCA2 exon 11 protein-termination-codon variants.
3
Pathogenic: PP4 (supporting) is met because the exact-variant clinical-history LR is 2.7664, above 2.08.
4
Pathogenic: PP5 (supporting) is met because ClinVar records an exact-variant ENIGMA expert-panel Pathogenic classification with three stars.
Final determination: The ENIGMA BRCA2 VCEP Version 1.2 Table 3 assigns Pathogenic when one very strong criterion and at least one strong criterion are met; PVS1 very strong plus PM5 strong satisfies this rule.
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 Met: exon 11 nonsense variant p.Glu1953Ter receives the ENIGMA Table 4 PVS1 assignment, with no exon-specific downgrade, so strength is very strong.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_specifications_table4_v1_2_2024_11_18 PMID:16683254
PS1 N/A Not applicable: c.5857G>T produces the PTC p.Glu1953Ter, whereas ENIGMA PS1 protein-change evidence is restricted to missense substitutions.
cspec vcep_specifications_v1_2_2024_11_18
PS2 N/A Not applicable: ENIGMA explicitly prohibits PS2 for BRCA2 because de novo occurrence has not been calibrated for these relatively common cancers.
cspec
PS3 Not assessed Not assessed: no exact calibrated protein-function assay or ENIGMA Table 9 PS3 assignment was found for c.5857G>T.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_specifications_table9_v1_2_2024_11_18 PMID:16683254
PS4 Not assessed Not assessed: qualifying PS4 requires OR >=4, p-value <=0.05, and a lower confidence limit above 2.0, but these case-control metrics are unavailable.
cspec PMID:16683254 PMID:23199084 vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001
PM1 N/A Not applicable: ENIGMA explicitly says not to use PM1, and residue 1953 lies outside approved domains aa 10-40 and 2481-3186.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
PM2 Not assessed Not assessed: the variant appears at 2/250950 alleles in all-comers gnomAD v2.1, but required non-cancer v2.1/v3.1 absence and depth data were unavailable.
cspec vcep_appendices_v1_2_2024_11_18 gnomad_v2 gnomad_v4
PM3 Not assessed Not assessed: no documented Fanconi anemia phenotype, second BRCA2 pathogenic variant, or phase evidence supports assignment of the ENIGMA PM3 point thresholds.
cspec
PM4 N/A Not applicable: this is a nonsense stop-gain variant, whereas ENIGMA PM4 is reserved for in-frame length changes or stop-loss variants and is explicitly not used.
cspec vcep_specifications_v1_2_2024_11_18
PM5 Met Met, strong: ENIGMA Table 4 pre-assigns PM5_Strong (PTC) for BRCA2 exon 11, which contains c.5857G>T.
cspec vcep_specifications_table4_v1_2_2024_11_18 vcep_specifications_v1_2_2024_11_18
PM6 N/A Not applicable: ENIGMA explicitly prohibits PM6 for BRCA2 because de novo occurrence has not been calibrated for these relatively common cancers.
cspec
PP1 Not assessed Not assessed: four affected relatives are reported, but no quantitative co-segregation LR is available to meet the ENIGMA PP1 thresholds, including LR ≥2.08 for supporting evidence.
cspec clinvar
PP2 N/A Not applicable: ENIGMA says not to use PP2 for BRCA2, and this variant is a nonsense PTC rather than a missense change.
cspec vcep_specifications_v1_2_2024_11_18
PP3 N/A Not applicable: p.(Glu1953Ter) is a nonsense truncation, outside PP3's calibrated computational scope regardless of available predictor scores.
cspec
PP4 Met Met, supporting: exact-variant clinical-history LR 2.7664 >= the ENIGMA PP4 Supporting threshold of 2.08.
cspec PMID:31853058
PP5 Met Met, supporting: exact-variant ClinVar expert-panel classification is Pathogenic with three-star review status.
clinvar cspec
BA1 Not assessed Not assessed: available all-comers gnomAD AFs are 7.97e-06 and 2.48e-06, but required non-cancer FAF data were unavailable for the VCEP >0.001 threshold.
cspec vcep_appendices_v1_2_2024_11_18 gnomad_v2 gnomad_v4
BS1 Not assessed Not assessed: reported all-comers maximum AFs are 1.76e-05 and 3.39e-06, but required non-cancer FAF values were unavailable for the VCEP >0.00002 threshold.
cspec vcep_appendices_v1_2_2024_11_18 gnomad_v2 gnomad_v4
BS2 Not assessed Not assessed: gnomAD shows zero homozygotes, but no qualifying phenotyped healthy-adult or Fanconi-Anemia-negative clinical observations were provided for BS2.
cspec vcep_appendices_v1_2_2024_11_18 gnomad_v2 gnomad_v4
BS3 Not assessed Not assessed: no exact calibrated protein-function assay or ENIGMA Table 9 BS3 assignment was found for c.5857G>T.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_specifications_table9_v1_2_2024_11_18 PMID:16683254
BS4 Not assessed Not assessed: no non-segregating affected relatives or benign-direction LR is available, with ENIGMA BS4 supporting evidence requiring LR ≤0.48.
cspec
BP1 N/A Not applicable: BP1 covers silent, missense, or in-frame variants, whereas c.5857G>T is the nonsense PTC p.Glu1953Ter.
cspec vcep_specifications_v1_2_2024_11_18
BP2 N/A Not applicable: the ENIGMA BRCA2 specification says BP2 is not used and restricts its application to the BS2 context.
cspec
BP3 N/A Not applicable: BP3 covers in-frame indels in functionless repetitive regions, but this variant is a nonsense stop-gain and the ENIGMA VCEP says not to use BP3.
cspec vcep_specifications_v1_2_2024_11_18
BP4 N/A Not applicable: p.(Glu1953Ter) is a nonsense truncation, outside BP4's calibrated computational scope regardless of available predictor scores.
cspec
BP5 Not met Not met: clinical-history LR 2.7664 <= 0.48? no, so it does not meet the ENIGMA BP5 Supporting threshold.
cspec PMID:31853058
BP6 Not met Not met: the exact-variant ClinVar expert-panel classification is Pathogenic, not Benign or Likely benign.
clinvar cspec
BP7 N/A Not applicable: p.(Glu1953Ter) is nonsense rather than synonymous or eligible intronic, so BP7 cannot be applied.
cspec
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