BRCA2 NM_000059.4:c.5238dupT (p.Asn1747Ter) is a frameshift variant in exon 11 resulting in a premature termination codon at position 1747. Loss of function is an established disease mechanism for BRCA2.1 Per ENIGMA BRCA2 Specifications Table 4 (v1.2, 2024-11-18), PTC variants in exon 11 are assigned PVS1 at very strong strength. NMD is predicted as the PTC occurs well upstream of the final exon.2 Per ENIGMA BRCA2 Specifications Table 4, exon 11 PTC variants also qualify for PM5_Strong (PTC), as exon 11 is not among the PM5_N/A exons (E6, E12, E27). Multiple proven pathogenic PTC variants have been observed in this exon.3 In ClinVar (Variation ID 37954), this variant is classified as Pathogenic with review status 'reviewed by expert panel' (ENIGMA), supported by 39 clinical laboratory submissions. PP5 is applied at supporting strength per the ClinVar 3-star expert panel override.4 The variant is absent from gnomAD v2.1 and present at extremely low frequency in gnomAD v4.1 (AF=1.86e-06, 3/1,610,822 alleles, grpmax FAF=6.8e-07). Clinical-history likelihood ratio is neutral (LR=1.717).5 Classification: Pathogenic. PVS1 (Very Strong) + PM5_Strong (PTC) satisfies ENIGMA Table 3 pathogenic combination rules (1 Very Strong + 1 Strong = Pathogenic).6
BRCA2
Final classification
Unclassified
BRCA2 c.5238dup · p.Asn1747Ter
BRCA2
BRCA2 NM_000059.4:c.5238dupT (p.Asn1747Ter) is a frameshift variant in exon 11 resulting in a premature termination codon at position 1747. Loss of function is an established disease mechanism for BRCA2.
Classification rationale
PVS1PM5PP5
Unclassified
BRCA2 c.5238dup
· exon NC_000013.10
PVS1 + PM5 + PP5
→
Unclassified
1
pvs1_gene_context
2
vcep_specifications_table4_v1_2_2024_11_18
3
vcep_specifications_table4_v1_2_2024_11_18
5
gnomad_v2 ↗gnomad_v4 ↗vcep_pmid_31853058_brca2_clinical_history_lr
6
vcep_specifications_v1_2_2024_11_18
Gene diagram
· NM_000059.4 · variants mapped to exon structure
BRCA2
NM_000059.4
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 9 assessed
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
✓
PVS1
very strong
Pathogenic
BRCA2 c.5238dupT is a frameshift variant in exon 11 resulting in a premature termination codon at p.Asn1747Ter. Loss of function is an established disease mechanism for BRCA2. Per ENIGMA BRCA2 Specifications Table 4, PTC variants in exon 11 are assigned PVS1 at very strong strength. NMD is predicted as the PTC is located well upstream of the last exon (exon 27). The variant is absent from gnomAD v2.1.
ENIGMA Table 4: BRCA2 exon 11 PTC → PVS1 (Very Strong)NMD predicted — PTC at codon 1747 in 48.1% exon 11far from last exon
✓
PM5
strong
Pathogenic
Per ENIGMA BRCA2 Specifications Table 4, PTC variants in exon 11 qualify for PM5_Strong (PTC). Exon 11 is not a PM5_N/A exon (PM5_N/A exons for BRCA2: E6, E12, E27 only). A PTC in exon 11 where other proven pathogenic PTC variants have been observed supports this additional weight.
ENIGMA Table 4: BRCA2 exon 11 PTC → PM5_Strong (PTC)
✓
PP5
supporting
Pathogenic
Expert panel Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) classified as Pathogenic.
ClinVar Variation ID 37954: Pathogenicreviewed by expert panel (ENIGMA)39 clinical laboratories classify as Pathogenic
Assessed · not applied
Pathogenic
PS4
No case-control study with p≤0.05 and OR≥4 is available for this variant.
PM2
The ENIGMA BRCA2 PM2 rule requires absence from gnomAD v2.1 (non-cancer, exome) AND v3.1 (non-cancer).
PP1
No co-segregation data or quantitative segregation likelihood ratio is available for this variant.
PP4
Per PMID:31853058 clinical-history likelihood ratio table, BRCA2 c.5238dupT has LR=1.717 (LOG(LR)=0.540, N_Probands=10).
Benign
BA1
BA1 requires FAF > 0.1% (FAF > 0.001) in gnomAD v2.1/v3.1 non-cancer.
BS1
BS1 requires FAF > 0.01% (Strong) or >0.002% (Supporting).
BS2
BS2 requires documented absence of Fanconi Anemia phenotype features with sufficient proband points per ENIGMA Table 8.
BS4
BS4 requires lack of segregation in affected family members, quantified by LR≤0.05 (Strong) or LR≤0.48 (Supporting).
BP5
Per PMID:31853058 clinical-history LR table, BRCA2 c.5238dupT has LR=1.717 which falls in the neutral zone (>0.48 and <2.08).
N/A · 16
PS1 · PS2 · PS3 · PM1 · PM3 · PM4 · PM6 · PP2 · PP3 · BS3 · BP1 · BP2 · BP3 · BP4 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 1.8624e-06; MAF= 0.00019%, 3/1610822 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.54695e-06; MAF= 0.00025%, 3/1177880 alleles, homozygotes = 0); grpmax FAF= 6.8e-07.
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
0.00019%
· 3 / 1,610,822
0 hom · FAF 6.8e-05%
0 hom · FAF 6.8e-05%
European (non-Finnish) 3 / 1,177,880 |
0.00025% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
In progress — evidence not uploaded yet.
Hotspots
This variant does not lie in a statistically significant hotspot.
Literature · how each cited paper was used
1papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 8 further PMIDs triaged but not cited — see Sources & References.
PMID PMID:25682074
Found
Structured finding pending for this record — see source link.
Applied to
→PVS1 supports · met
Sources & reference links
9Sources
Triaged references · 8 PMIDs not cited in assessment
20878484 ↗
A new mutation of BRCA2 gene in an Italian healthy woman with familial breast cancer history.
ONCOKB
24312913 ↗
A comprehensive focus on global spectrum of BRCA1 and BRCA2 mutations in breast cancer.
ONCOKB
11802209 ↗
Comprehensive analysis of 989 patients with breast or ovarian cancer provides BRCA1 and BRCA2 mutation profiles and frequencies for the German population.
CLINVAR
20104584 ↗
Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study.
CLINVAR
25682074 ↗
Prevalence of BRCA1 and BRCA2 germline mutations in patients with triple-negative breast cancer.
CLINVAR