Classification rationale

PVS1PM5PP5 Pathogenic

BRCA2 c.7908T>A nonsense · exon 17

PVS1 very strong: the ENIGMA exon 17 rule applies to this upstream BRCA2 protein-truncating variant. PM5 strong: ENIGMA assigns the exon 17 PTC code PM5_Strong (PTC). PP5 supporting: an exact-match ENIGMA expert-panel ClinVar classification is Pathogenic.

PVS1 + PM5 + PP5 → Pathogenic

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

Gene diagram · NM_000059.4 · variants mapped to exon structure

BRCA2 NM_000059.4

Fetching transcript structure from UCSC…

Applied criteria · 3 applied · 13 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 3

Strength Supporting Moderate Strong Very strong

PVS1 very strong Pathogenic

Met, very strong: ENIGMA Table 4 assigns PVS1 to BRCA2 exon 17 PTCs, and p.Cys2636Ter truncates 783 of 3418 amino acids upstream of the terminal exon.

The case normalization identifies NM_000059.4:c.7908T>A as NP_000050.3:p.(Cys2636Ter)/p.(C2636*), a nonsense change, with the predicted protein ending at residue 2636 while the reference ends at residue 3418.Specifications Table 4 lists BRCA2 exon 17, coding interval c.7806-c.7976, PTC code PVS1, and exon 17 protein interval p.2602-p.2659; c.7908 lies within this exon.The ENIGMA specification defines PVS1_VariableWeight for null variants in genes where loss of function is a known disease mechanism and directs PTC variants to the exon-specific Table 4 decision tree.

cspec ↗

PM5 strong Pathogenic

Met, Strong: ENIGMA Table 4 assigns PM5_Strong (PTC) to BRCA2 exon 17, which contains c.7908.

Specifications_Table4_V1.2_2024-11-18.xlsx.txt lists BRCA2 exon 17 as c.7806-c.7976 and assigns PVS1 for coding PTC variants plus PM5_Strong (PTC).c.7908 falls within the exon 17 coding interval, and the case normalization identifies the consequence as nonsense with p.Cys2636Ter.The ENIGMA Appendix D rule states that PM5(PTC) is exon-specific, applies to nonsense and frameshift changes meeting PVS1, and is distinct from classic same-residue missense PM5.

PP5 supporting Pathogenic

Met, Supporting: exact ClinVar variation 52433 has an ENIGMA expert-panel Pathogenic classification, satisfying the requested PP5 rule.

ClinVar variation 52433 exactly matches NM_000059.4(BRCA2):c.7908T>A (p.Cys2636Ter).ClinVar reports Pathogenic with review status reviewed by expert panel and three review stars; the expert panel is ENIGMA.Ordinary laboratory submissions and aggregate labels were not used to trigger PP5; only the exact-variant expert-panel assertion was used.

clinvar ↗cspec ↗

Assessed · not applied · 3 not met · 10 not assessed

Pathogenic

PS3 Not assessed: no calibrated damaging functional-assay result was found for c.7908T>A, p.Cys2636Ter, or p.C2636*.

PS4 Not assessed: no variant-specific case-control OR, confidence interval, p-value, or qualifying affected/control counts were available for the PS4 OR >=4 threshold.

PM2 Not assessed: the variant is absent from both required non-cancer gnomAD datasets, but the ENIGMA PM2 prerequisite of regional average read depth at least 25 is undocumented.

PM3 Not assessed: no Fanconi Anemia phenotype, same-gene pathogenic co-variant, or verified phase is documented for PM3 application.

PP1 Not assessed: no variant-specific pedigree or quantitative segregation LR was available to compare with the PP1 threshold of LR >=2.08.

PP4 Not assessed: the gene-specific clinical-history table has no c.7908T>A row, so no combined LR can be compared with the PP4 >=2.08 threshold.

Benign

BA1 Not met: the variant is absent from the governing non-cancer gnomAD datasets, so no filter allele frequency exceeds the ENIGMA BA1 threshold of 0.1%.

BS1 Not met: the variant is absent from both governing non-cancer gnomAD datasets, so its frequency does not reach the ENIGMA BS1 threshold of 0.01%.

BS2 Not assessed: no individual-level homozygote, healthy-carrier, age, follow-up, or Fanconi Anemia phenotype data are available to assign ENIGMA BS2 points.

BS3 Not assessed: no calibrated benign functional-assay result was found for c.7908T>A, p.Cys2636Ter, or p.C2636*.

BS4 Not assessed: no variant-specific non-segregation data or quantitative LR was available to compare with the BS4 supporting threshold of LR <=0.48.

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

BP6 Not met: exact ClinVar variation 52433 is Pathogenic by an ENIGMA expert panel, not Benign or Likely Benign for BP6.

N/A · 12 PS1 · PS2 · PM1 · PM4 · PM6 · PP2 · PP3 · BP1 · BP2 · BP3 · BP4 · BP7

Research & evidence

Population frequency · supports pathogenic

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Pathogenic (4 clinical laboratories) and as Pathogenic by Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) (expert panel). (ClinVarID = 52433)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). BayesDel score = 0.466048.

SpliceAI ↗

Functional Likely Oncogenic

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

9Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 8 PMIDs not cited in assessment

10570174 ↗ Truncated BRCA2 is cytoplasmic: implications for cancer-linked mutations. ONCOKB

11239455 ↗ BRCA2 is required for homology-directed repair of chromosomal breaks. ONCOKB

20878484 ↗ A new mutation of BRCA2 gene in an Italian healthy woman with familial breast cancer history. ONCOKB

22193408 ↗ BRCA1 and BRCA2: different roles in a common pathway of genome protection. ONCOKB

24312913 ↗ A comprehensive focus on global spectrum of BRCA1 and BRCA2 mutations in breast cancer. ONCOKB

20104584 ↗ Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study. CLINVAR

31672839 ↗ Management of patients with increased risk for familial pancreatic cancer: updated recommendations from the International Cancer of the Pancreas Screening (CAPS) Consortium. CLINVAR

12692171 ↗ American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility. CLINVAR

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