The BRCA2 NM_000059.4:c.5350_5351del (NP_000050.3:p.(Asn1784HisfsTer2); p.(N1784Hfs*2)) variant has been reported in ClinVar with an expert-panel Pathogenic classification, and curated somatic review resources describe it as a likely loss-of-function BRCA2 alteration.1 This variant is present in population databases at low frequency, including 1/31,198 alleles in gnomAD v2.1 (AF 3.20533e-05) and 41/1,612,540 alleles in gnomAD v4.1 (AF 2.54257e-05; grpmax FAF 2.315e-05), which is too high for PM2 but far below BA1.2 The variant is a frameshift deletion predicted to truncate BRCA2 after codon 1784, and the ENIGMA BRCA2 exon-level table designates exon 11 as eligible for full-strength PVS1 and PM5_Strong (PTC).3 Clinical-history modeling for BRCA2 reports a likelihood ratio of 812.95 from 42 probands, exceeding the ENIGMA Very Strong PP4 threshold of 350; SpliceAI shows no separate splice signal (max delta 0.00).4
BRCA2
Final classification
Pathogenic
BRCA2 c.5350_5351del · p.Asn1784HisfsTer2
BRCA2
The BRCA2 NM_000059.4:c.5350_5351del (NP_000050.3:p.(Asn1784HisfsTer2); p.(N1784Hfs*2)) variant has been reported in ClinVar with an expert-panel Pathogenic classification, and curated somatic review resources describe it as a likely loss-of-function BRCA2 alteration.
ENIGMA BRCA1 and BRCA2 Specification v1.2.0 Table 3 criteria-combination framework (CSPEC/VCEP official framework override).
Classification rationale
PVS1PM5PP4PP5
Pathogenic
BRCA2 c.5350_5351del
PVS1 + PM5 + PP4 + PP5
→
Pathogenic
3
cspec ↗vcep_specifications_table4_v1_2_2024_11_18pvs1_gene_contextpvs1_variant_assessment
4
vcep_pmid_31853058_brca2_clinical_history_lrPMID:31853058 ↗spliceai ↗cspec ↗
Gene diagram
· NM_000059.4 · variants mapped to exon structure
BRCA2
NM_000059.4
Fetching transcript structure from UCSC…
Applied criteria · 4 applied · 11 assessed
Applied · 4
Strength
Supporting
Moderate
Strong
Very strong
✓
PVS1
very strong
Pathogenic
This variant is a frameshift deletion predicted to produce p.(Asn1784HisfsTer2), truncating BRCA2 shortly after codon 1784. In the ENIGMA BRCA2 specification, loss of function is an established disease mechanism, and exon 11 is designated as PVS1-applicable; therefore full-strength PVS1 is met.
NM_000059.4:c.5350_5351del predicts NP_000050.3:p.(Asn1784HisfsTer2)BRCA2 exon 11ENIGMA Table 4 marks exon 11 as PVS1
✓
PM5
strong
Pathogenic
In the BRCA2 ENIGMA framework, PM5 is repurposed for truncating variants. This frameshift creates a premature termination codon in exon 11, and ENIGMA Table 4 assigns exon 11 a PM5_Strong (PTC) designation, so PM5 is met at Strong strength.
Variant is a PTC-generating frameshiftBRCA2 exon 11 is annotated PM5_Strong (PTC)
✓
PP4
very strong
Pathogenic
This variant has a BRCA2 clinical-history likelihood ratio of 812.95 based on 42 probands in the ENIGMA-supported Li et al. dataset. This value is above the Very Strong threshold of 350, so PP4 is met at Very Strong strength.
HGVS_Nucleotide c.5350_5351delAALR 812.9481905745328N_Probands 42
Assessed · not applied
Pathogenic
PS3
No variant-specific calibrated functional study assigning PS3 for this variant was identified.
PS4
The variant has been reported clinically, but no qualifying case-control study demonstrating a significant enrichment in affected individuals with p-value ≤0.05 and odds ratio ≥4 was identified.
PM2
This variant is not absent from population databases.
PM3
No evidence was identified showing this variant in trans with another BRCA2 variant in an individual with phenotype consistent with BRCA2-related Fanconi anemia.
PP1
No quantitative co-segregation data were identified for this variant, so PP1 cannot be assessed from the available evidence.
Benign
BA1
Population frequency is well below the BA1 threshold.
BS1
Available population data do not support BS1.
BS2
No qualifying observations in individuals lacking features of BRCA2-related Fanconi anemia were identified to support BS2.
BS3
No variant-specific calibrated functional study showing no damaging effect was identified for this variant.
BS4
No quantitative lack-of-segregation likelihood-ratio data were identified for this variant, so BS4 cannot be assessed.
BP5
The available multifactorial clinical-history evidence does not support BP5.
N/A · 13
PS1 · PS2 · PM1 · PM4 · PM6 · PP2 · PP3 · BP1 · BP2 · BP3 · BP4 · BP6 · BP7
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 2.54257e-05; MAF= 0.00254%, 41/1612540 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 4.80507e-05; MAF= 0.00481%, 3/62434 alleles, homozygotes = 0); grpmax FAF= 2.315e-05.
v2.1
This variant is present in gnomAD v2.1 (AF= 3.20533e-05; MAF= 0.00321%, 1/31198 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 6.52912e-05; MAF= 0.00653%, 1/15316 alleles, homozygotes = 0).
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0025%
· 41 / 1,612,540
0 hom · FAF 0.0023%
0 hom · FAF 0.0023%
Remaining individuals 3 / 62,434 |
0.0048% |
European (non-Finnish) 37 / 1,179,132 |
0.0031% |
African/African American 1 / 74,774 |
0.0013% |
+ 7 not observed (Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish)
gnomAD v2.1
0.0032%
· 1 / 31,198
0 hom
0 hom
European (non-Finnish) 1 / 15,316 |
0.0065% |
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Pathogenic (35 clinical laboratories) and as Uncertain significance (1 clinical laboratory) and as Pathogenic by Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) (expert panel). (ClinVarID = 37959)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
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.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV104701329, n = 1 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Literature · how each cited paper was used
4papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 9 further PMIDs triaged but not cited — see Sources & References.
PMID PMID:31853058
Found
Structured finding pending for this record — see source link.
Applied to
→PP4 supports · met
PMID cspec
Found
Structured finding pending for this record — see source link.
Applied to
→PM5 supports · met
→PP4 supports · met
→PP5 supports · met
→PVS1 supports · met
PMID vcep_pmid_31853058_brca2_clinical_history_lr
Found
Structured finding pending for this record — see source link.
Applied to
→PP4 supports · met
PMID vcep_specifications_table4_v1_2_2024_11_18
Found
Structured finding pending for this record — see source link.
Applied to
→PM5 supports · met
→PVS1 supports · met
Sources & reference links
9Sources
Triaged references · 9 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
10486320 ↗
The contribution of germline BRCA1 and BRCA2 mutations to familial ovarian cancer: no evidence for other ovarian cancer-susceptibility genes.
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
22006311 ↗
Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR