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
BRCA2
Final classification
Pathogenic
BRCA2 c.5946del · p.Ser1982ArgfsTer22
BRCA2
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 ↗
Gene diagram
· NM_000059.3 · variants mapped to exon structure
BRCA2
NM_000059.3
Fetching transcript structure from UCSC…
Applied criteria · 4 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
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.
PMID PMID:31853058
Found
Structured finding pending for this record — see source link.
Applied to
→PP4 supports · met
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