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BRCA2
Final classification
Uncertain Significance
PVS1
BRCA2
c.2164A>T
p.Lys722Ter
nonsense · exon 11
Gene context NCBI Gene ↗ OncoKB ↗

BRCA2 encodes a DNA repair protein that maintains genome stability by repairing double-strand breaks through homologous recombination and by protecting DNA replication forks. It acts as a tumor suppressor, and inherited loss-of-function changes cause hereditary breast and ovarian cancer syndrome, with elevated lifetime risks of breast, ovarian, prostate, and pancreatic cancers; biallelic changes cause Fanconi anemia complementation group D1. Reduced or altered BRCA2 activity is implicated in multiple tumor types, and PARP inhibitors are an approved treatment for BRCA2-associated ovarian and breast cancers.

This variant

BRCA2 loss-of-function causes hereditary breast and ovarian cancer syndrome, and this nonsense change is predicted to trigger nonsense-mediated decay, matching the gene's established disease mechanism. Under the ENIGMA VCEP rules, PVS1 (Very Strong) alone does not reach the evidence threshold for a pathogenic call, so this variant remains classified as Uncertain Significance.

Transcript
NM_000059.4
HGVS · transcript:coding
NM_000059.4:c.2164A>T
GRCh38
chr13:32336519 A>T
GRCh37
chr13:32910656 A>T
Basis Only PVS1 (Very Strong) is met; the ENIGMA VCEP rule requires Very Strong plus Strong/Moderate/two Supporting for a pathogenic call, so this variant is classified as Uncertain Significance. ▾
Only PVS1 (Very Strong) is met; the ENIGMA VCEP rule requires Very Strong plus Strong/Moderate/two Supporting for a pathogenic call, so this variant is classified as Uncertain Significance.
Classification rationale
PVS1 Uncertain Significance
BRCA2 c.2164A>T nonsense · exon 11

PVS1 (Very Strong): c.2164A>T creates the premature termination codon p.(Lys722Ter) in BRCA2 exon 11, predicted to trigger nonsense-mediated decay. Final classification: Uncertain Significance — PVS1 (Very Strong) alone is met, and the ENIGMA VCEP rule requires additional Strong, Moderate, or two Supporting criteria for a pathogenic call.

PVS1 → Uncertain Significance
Gene diagram · NM_000059.4 · variants mapped to exon structure
BRCA2 NM_000059.4
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 14 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 · 1
Strength Supporting Moderate Strong Very strong
✓
PVS1 very strong Pathogenic
Met (Very Strong): this nonsense change creates p.(Lys722Ter) in exon 11, predicted to trigger nonsense-mediated decay.
cspec (ENIGMA BRCA1/BRCA2 Specification v1.2): PVS1 defaultStrength 'Pathogenic Very Strong' for null variants (nonsense, frameshift, canonical splice site +/-1,2, initiation codon, single/multi-exon deletion) in BRCA2, applied per PVS1 flowchart considering clinically important functional domains.pvs1_gene_context: germline_disease_context_found=true, lof_mechanism_supported=true, pvs1_gene_gate='eligible' because official CSPEC/VCEP criteria for BRCA2 include PVS1 guidance, establishing LOF as a recognized disease mechanism.pvs1_variant_assessment: consequence_class='nonsense', variant_bucket='nonsense', suggested_default_strength='PVS1', framework_source PMC6185798 (ClinGen SVI PVS1 recommendations) applied since gene-level LOF eligibility is established.
cspec ↗pvs1_generic_framework ↗
Assessed · not applied · 4 not met · 10 not assessed
Pathogenic
PS3 Not assessed: no variant-specific functional assay result for p.(Lys722Ter) was available.
PS4 Not assessed: no case-control enrichment data exist for this variant.
PM2 Not assessed: the variant is absent from gnomAD v2.1, but the required average read depth of at least 25 was not reported.
PM3 Not assessed: no Fanconi anemia phenotype, second pathogenic BRCA2 variant, or phase information was available.
PM5 Not assessed: no previously classified pathogenic exon-11 premature termination codon variant was identified as a comparator.
PP1 Not assessed: no quantitative co-segregation data were available (LR of at least 2.08:1 required).
PP3 Not met: SpliceAI max delta 0.01 is below the 0.2 threshold for predicted splice impact.
PP4 Not assessed: no clinical-history likelihood ratio is available for this variant.
Benign
BA1 Not met: the variant is absent from gnomAD v2.1 and v4.1, with no allele frequency above the 0.1% threshold.
BS1 Not met: absent from gnomAD, with no allele frequency above the 0.002% BS1_Supporting threshold.
BS2 Not assessed: no homozygous carriers or carrier phenotype data were available.
BS4 Not assessed: no co-segregation data demonstrating lack of segregation were available (LR of 0.48:1 or lower required).
BP4 Not met: BP4 is scoped to missense, silent, or intronic variants, and this is a nonsense change (SpliceAI max delta 0.01).
BP5 Not assessed: no clinical-history likelihood ratio is available for this variant.
N/A · 13 PS1 · PS2 · PM1 · PM4 · PM6 · PP2 · PP5 · BS3 · BP1 · BP2 · BP3 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1 screenshot
gnomAD v4.1
gnomAD v2.1 screenshot
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 screenshot
ClinVar
This variant is absent from ClinVar.
ClinVar ↗
SpliceAI screenshot
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). BayesDel score = 0.290735.
SpliceAI ↗
Functional / OncoKB screenshot
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 screenshot
COSMIC
Cancer hotspots screenshot
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 · 5 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