The BRCA2 c.5946del (p.(Ser1982ArgfsTer22)) variant has been observed in somatic cancers in COSMIC (COSV66447676, n=10) and has been reported in ClinVar as pathogenic with expert-panel review by the ClinGen ENIGMA BRCA1/2 Variant Curation Expert Panel.1 This variant is present in population databases, including gnomAD v2.1 at AF 0.000276509 (78/282088 alleles) and gnomAD v4.1 at AF 0.000139416 (225/1613878 alleles), with highest frequency in the Ashkenazi Jewish population; therefore it is not absent from controls and does not meet PM2.2 Clinical-history evidence supports pathogenicity: in the BRCA2 likelihood-ratio dataset, c.5946delT has an LR of 31.79 from 149 probands, exceeding the ENIGMA PP4_Strong threshold of 18.7.3 Computational and predicted consequence data show a frameshift leading to p.(Ser1982ArgfsTer22), while SpliceAI predicts no additional splice alteration (max delta 0.00); under the BRCA2 ENIGMA exon-specific truncating-variant framework, exon 11 supports PVS1 and PM5_Strong for this protein-truncating variant.4
Final classification
Pathogenic
PVS1PM5PP4PP5
BRCA2
c.5946del
p.Ser1982ArgfsTer22
This variant
The BRCA2 c.5946del (p.(Ser1982ArgfsTer22)) variant has been observed in somatic cancers in COSMIC (COSV66447676, n=10) and has been reported in ClinVar as pathogenic with expert-panel review by the ClinGen ENIGMA BRCA1/2 Variant Curation Expert Panel.
ENIGMA BRCA1 and BRCA2 Specification v1.2 Table 3 criteria-combination framework (official ClinGen/CSPEC final-classification framework).
Classification rationale
PVS1PM5PP4PP5
Pathogenic
BRCA2 c.5946del
PVS1 + PM5 + PP4 + PP5
→
Pathogenic
3
vcep_pmid_31853058_brca2_clinical_history_lrPMID:31853058 ↗cspec ↗
4
pvs1_variant_assessmentspliceai ↗vcep_specifications_table4_v1_2_2024_11_18cspec ↗
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_000059.3 · variants mapped to exon structure
BRCA2
NM_000059.3
Fetching transcript structure from UCSC…
Applied criteria · 4 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 · 4
Strength
Supporting
Moderate
Strong
Very strong
PVS1
very strong
Pathogenic
This variant is a frameshift deletion predicted to cause p.(Ser1982ArgfsTer22) / p.(S1982Rfs*22). BRCA2 loss of function is an established disease mechanism, and the BRCA2 ENIGMA Table 4 exon 11 rule assigns PVS1 for truncating variants in this exon, supporting PVS1 at very strong strength.
Predicted protein consequence p.(Ser1982ArgfsTer22)BRCA2 exon 11 truncating-variant PVS1 rule
PM5
strong
Pathogenic
This variant creates a premature termination codon in BRCA2 exon 11. In the BRCA2 ENIGMA exon-level Table 4, exon 11 is designated PM5_Strong for PTC variants, indicating that different proven pathogenic truncating variants have been observed in this exon and supporting PM5 at strong strength.
PM5 repurposed PTC logic for BRCA2Exon 11 Table 4 assignment PM5_Strong (PTC)
PP4
strong
Pathogenic
In the BRCA2 clinical-history likelihood-ratio dataset, this variant is listed as c.5946delT with LR 31.79 from 149 probands. This exceeds the BRCA2 ENIGMA PP4_Strong threshold of 18.7, supporting PP4 at strong strength.
Clinical-history LR 31.79339476332673149 probands
Assessed · not applied
· 4 not met · 7 not assessed
Pathogenic
PS3
No calibrated variant-specific functional assay result for c.5946del was identified from the BRCA2 ENIGMA functional evidence sources reviewed.
PS4
This founder variant has been widely reported in affected individuals, but no reviewed case-control analysis with explicit odds ratio meeting the BRCA2 ENIGMA PS4 requirement was identified here.
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 a phenotype consistent with BRCA2-related Fanconi anemia.
PP1
No quantitative co-segregation likelihood ratio meeting BRCA2 ENIGMA PP1 thresholds was identified for this variant.
Benign
BA1
The BRCA2 ENIGMA BA1 threshold requires non-founder population filter allele frequency greater than 0.001.
BS1
The BRCA2 ENIGMA BS1 rule is based on non-founder population filter allele frequency.
BS2
No point-based BRCA2 ENIGMA BS2 evidence was identified showing this variant in individuals without features of BRCA2-related Fanconi anemia under the framework rules.
BS3
No calibrated benign functional assay result for c.5946del was identified in the reviewed BRCA2 functional evidence sources.
BS4
No quantitative non-segregation likelihood ratio meeting BRCA2 ENIGMA BS4 thresholds was identified for this variant.
BP5
The variant-specific BRCA2 clinical-history likelihood ratio is 31.79, which is in the pathogenic direction and well above the BP5 thresholds of 0.48, 0.23, 0.05, and 0.00285.
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= 0.000139416; MAF= 0.01394%, 225/1613878 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.00533856; MAF= 0.53386%, 158/29596 alleles, homozygotes = 0); grpmax FAF= 2.154e-05.
v2.1
This variant is present in gnomAD v2.1 (AF= 0.000276509; MAF= 0.02765%, 78/282088 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.00588576; MAF= 0.58858%, 61/10364 alleles, homozygotes = 0); grpmax FAF= 5.39e-05.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.014%
· 225 / 1,613,878
0 hom · FAF 0.0022%
0 hom · FAF 0.0022%
Ashkenazi Jewish 158 / 29,596 |
0.53% |
Remaining individuals 31 / 62,478 |
0.05% |
European (non-Finnish) 35 / 1,179,918 |
0.003% |
African/African American 1 / 74,912 |
0.0013% |
+ 6 not observed (Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian)
gnomAD v2.1
0.028%
· 78 / 282,088
0 hom · FAF 0.0054%
0 hom · FAF 0.0054%
Ashkenazi Jewish 61 / 10,364 |
0.59% |
Remaining individuals 3 / 7,180 |
0.042% |
European (non-Finnish) 14 / 128,890 |
0.011% |
+ 5 not observed (African/African American, Admixed American, East Asian, European (Finnish), South Asian)
ClinVar
This variant has been reported in ClinVar as Pathogenic (67 clinical laboratories) and as pathogenic (1 clinical laboratory) and as Pathogenic by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 9325)
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; COSV66447676, n = 10 times).
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. 9 further PMIDs triaged but not cited — see Sources & references.
Li et al. 2020 BRCA1/2 clinical-history likelihood-ratio model
Found
Structured finding pending for this record — see source link.
Applied to
→PP4
strong
Sources & reference links
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
10417300 ↗
De novo BRCA1 mutation in a patient with breast cancer and an inherited BRCA2 mutation.
CLINVAR
14559878 ↗
Shared genetic susceptibility to breast cancer, brain tumors, and Fanconi anemia.
CLINVAR
11466700 ↗
The frequency of founder mutations in the BRCA1, BRCA2, and APC genes in Australian Ashkenazi Jews: implications for the generality of U.S. population data.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR