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NM_000059.4:c.8107dup
p.Thr2703AsnfsTer3 · BRCA2
ClinGen ENIGMA BRCA1 and BRCA2 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for BRCA2 Version 1.2 · v1.2
0%
complete
Final classification
Pathogenic
PVS1PM5
BRCA2
c.8107dup
p.Thr2703AsnfsTer3
frameshift · exon 18
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

This BRCA2 loss-of-function variant is relevant to hereditary breast and ovarian cancer syndrome because BRCA2 tumor-suppressor activity is required for homologous-recombination DNA repair and replication-fork protection.

Transcript
NM_000059.4
HGVS · transcript:coding
NM_000059.4:c.8107dup
GRCh38
chr13:32363306 G>GA
GRCh37
chr13:32937443 G>GA
Pathogenic: PVS1 (very strong) plus PM5 (strong) satisfies the ENIGMA BRCA2 Table 3 combination rule.
Classification rationale
PVS1PM5 Pathogenic
BRCA2 c.8107dup frameshift · exon 18

PVS1 Very Strong: the exon 18 frameshift creates a premature stop upstream of the ENIGMA NMD escape boundary. PM5 Strong: ENIGMA Table 4 assigns PM5_Strong (PTC) to genomic premature termination codons in BRCA2 exon 18.

PVS1 + PM5 → 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 · 2 applied · 11 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 · 2
Strength Supporting Moderate Strong Very strong
PVS1 very strong Pathogenic
Met, very strong: c.8107dup is an exon 18 frameshift with a premature stop at p.2705, upstream of the VCEP's c.9600 NMD escape boundary.
Case normalization: NM_000059.4:c.8107dup produces NP_000050.3:p.(Thr2703AsnfsTer3), also p.(T2703Nfs*3), with consequence class frameshift.ENIGMA Specifications Table 4, BRCA2 E18 row: PVS1 is assigned for protein-termination-codon variants; the row's PTC column is PVS1.ENIGMA Specifications v1.2, PVS1 criterion: null variants including frameshift variants in a gene where loss of function is a known disease mechanism are evaluated according to the PVS1 flowchart and Table 4.
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗vcep_specifications_table4_v1_2_2024_11_18 ↗
PM5 strong Pathogenic
Met, Strong: ENIGMA Table 4 preassigns PM5_Strong (PTC) to BRCA2 exon 18, where this genomic frameshift creates a premature termination codon.
Variant normalization identifies NM_000059.4:c.8107dup as a frameshift producing p.(Thr2703AsnfsTer3) / p.(T2703Nfs*3), a genomic PTC consequence.Specifications_Table4_V1.2_2024-11-18.xlsx, BRCA2 E18 row: PVS1 | PTC | PM5_Strong (PTC).ENIGMA Specifications v1.2 states that PM5_VariableWeight (PTC) is for a PTC variant in an exon where a different proven pathogenic PTC variant has been seen, is used for additional weight for PVS1-annotated PTC variants, applies only to genomic PTC changes, and is weighted by exon.
vcep_specifications_table4_v1_2_2024_11_18 ↗vcep_specifications_v1_2_2024_11_18 ↗cspec ↗
Assessed · not applied · 0 not met · 11 not assessed
Pathogenic
PS3 Not assessed: no variant-specific calibrated assay result or pre-assigned PS3 code was found for BRCA2 c.8107dup in the governing ENIGMA sources.
PS4 Not assessed: no variant-specific case-control p-value, odds ratio, and confidence interval were available to evaluate the ENIGMA PS4 requirements.
PM3 Not assessed: no Fanconi Anemia phenotype, BRCA2 co-variant, phase, or PM3 point observations are available for this variant.
PP1 Not assessed: no quantitative co-segregation LR or affected-family segregation data is available to compare with the PP1 threshold of LR ≥2.08:1.
PP4 Not assessed: the required BRCA2 clinical-history table has no row for this variant, so no combined clinical likelihood ratio can be compared with PP4 thresholds.
Benign
BA1 Not assessed: the variant is absent from both required non-cancer datasets, but FAF, read depth, and quality-control values needed for BA1 are unavailable.
BS1 Not assessed: both required non-cancer datasets report absence, but FAF, read depth, and quality-control values needed for BS1 are unavailable.
BS2 Not assessed: no qualifying healthy-adult observation or ENIGMA BS2 point assignment is available for this variant.
BS3 Not assessed: no variant-specific calibrated assay result or pre-assigned BS3 code was found for BRCA2 c.8107dup in the governing ENIGMA sources.
BS4 Not assessed: no quantitative non-segregation LR or affected-family data is available to compare with the BS4 Supporting threshold of LR ≤0.48:1.
BP5 Not assessed: no variant-level combined clinical likelihood ratio was found for comparison with the ENIGMA BP5 <=0.48:1 supporting threshold.
N/A · 15 PS1 · PS2 · PM1 · PM2 · PM4 · PM6 · PP2 · PP3 · PP5 · BP1 · BP2 · BP3 · BP4 · BP6 · BP7
Research & evidence
Population frequency · supports pathogenic
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 = 0.04).
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