About BRCA2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRCA2 c.5946del, p.(Ser1982ArgfsTer22)
Classification
Pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.
Pathogenic.A pathogenic classification under the recorded framework.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
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.
01The reasoning
How it was classified
The recorded framework is ClinGen BRCA2 VCEP v1.2.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 4
Benign evidence criteria: 0
Pathogenic criteria applied · 4
PVS1Very strong
PVS1 · very strong
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.
PM5Strong
PM5 · strong
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.
PP4Strong
PP4 · strong
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.
PP5Supporting
PP5 · supporting
Expert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Pathogenic.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Pathogenic
ENIGMA BRCA1 and BRCA2 Specification v1.2 Table 3 criteria-combination framework (official ClinGen/CSPEC final-classification framework).
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
225 / 1,613,878 alleles
gnomAD v4.1: 225 / 1,613,878 alleles. Recorded AF 0.000139416. Recorded homozygote count 0.
gnomAD 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.
No listed criterion applied
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
68 reported laboratory submissions
67 Pathogenic · 1 pathogenic.
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
10 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV66447676, n = 10 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen BRCA2 VCEP v1.2.0, with the data and sources behind each one.
28 criteria with recorded statuses: 4 met · 4 not met · 7 not assessed · 13 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
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.
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.
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.
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.
No criteria match.
Met · 4
PVS1 Very strongThis 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. Details ▾Hide ▴
Rule
ENIGMA BRCA2 v1.2 Table 4 exon 11: PVS1 for PTC/truncating variants
Evidence considered
- Predicted protein consequence p.(Ser1982ArgfsTer22)
- BRCA2 exon 11 truncating-variant PVS1 rule
Sources
PM5 StrongThis 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. Details ▾Hide ▴
Rule
ENIGMA BRCA2 v1.2 Table 4 exon 11: PM5_Strong (PTC)
Evidence considered
- PM5 repurposed PTC logic for BRCA2
- Exon 11 Table 4 assignment PM5_Strong (PTC)
Sources
PP4 StrongIn 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. Details ▾Hide ▴
Rule
PP4_Strong if LR >= 18.7
Evidence considered
- Clinical-history LR 31.79339476332673
- 149 probands
Sources
Not met · 4 · evaluated, threshold not reached
PM2 This variant is not absent from population databases. It is present in gnomAD v2.1 at AF 0.000276509 (78/282088 alleles) and in gnomAD v4.1 at AF 0.000139416 (225/1613878 alleles), so the BRCA2 ENIGMA PM2 requirement for absence from controls is not met. Details ▾Hide ▴
Rule
PM2_Supporting requires absence from controls
Evidence considered
- gnomAD v2.1 AF 0.000276509
- gnomAD v4.1 AF 0.000139416
Sources
BA1 The BRCA2 ENIGMA BA1 threshold requires non-founder population filter allele frequency greater than 0.001. The observed grpmax founder filter allele frequency is 5.39e-05 in gnomAD v2.1 and 2.154e-05 in gnomAD v4.1, both below 0.001, so BA1 is not met. Details ▾Hide ▴
Rule
BA1 requires non-founder FAF > 0.001
Evidence considered
- gnomAD v2.1 grpmax FAF 5.39e-05
- gnomAD v4.1 grpmax FAF 2.154e-05
Sources
BS1 The BRCA2 ENIGMA BS1 rule is based on non-founder population filter allele frequency. Although this founder variant is enriched in the Ashkenazi Jewish population, the reviewed data do not show a qualifying non-founder FAF above 0.00002 or 0.0001, so BS1 is not met. Details ▾Hide ▴
Rule
BS1 requires qualifying non-founder FAF threshold
Evidence considered
- Founder-enriched Ashkenazi Jewish frequency
- No qualifying non-founder FAF demonstrated
Sources
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. BP5 is therefore not met. Details ▾Hide ▴
Rule
BP5 requires LR <= 0.48, with stronger benign weights at lower LR
Evidence considered
- Clinical-history LR 31.79339476332673
Sources
Not assessed · 7 · no assessment recorded
PS3 No calibrated variant-specific functional assay result for c.5946del was identified from the BRCA2 ENIGMA functional evidence sources reviewed. General BRCA2 loss-of-function literature supports the disease mechanism, but it does not provide a variant-specific PS3 assignment here. Details ▾Hide ▴
Rule
PS3 requires well-established variant-specific functional evidence
Evidence considered
- No exact c.5946del/Table 9 match identified
- OncoKB-linked literature provides general BRCA2 loss-of-function context
Still missing
- No exact-variant calibrated PS3 assignment was identified in the reviewed BRCA2 functional resources.
Sources
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. Available observation data therefore do not support a direct PS4 assignment in this pass. Details ▾Hide ▴
Rule
PS4 requires significantly increased prevalence in affected individuals versus controls
Evidence considered
- ClinVar expert-panel pathogenic classification
- Published reports of this founder variant
Still missing
- A validated case-control comparison with ancestry-matched controls and qualifying odds ratio was not extracted.
Sources
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. PM3 was therefore not assessed. Details ▾Hide ▴
Rule
PM3 in BRCA2 is reserved for recessive Fanconi-anemia context
Still missing
- No BRCA2-related Fanconi anemia proband and in-trans data were identified.
Sources
PP1 No quantitative co-segregation likelihood ratio meeting BRCA2 ENIGMA PP1 thresholds was identified for this variant. Segregation evidence was therefore not assessed. Details ▾Hide ▴
Rule
PP1 requires quantitative co-segregation evidence
Evidence considered
- No usable quantitative segregation metric identified
Still missing
- No variant-specific segregation LR or pedigree-based PP1 calculation was identified.
Sources
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. BS2 was therefore not assessed. Details ▾Hide ▴
Rule
BS2 in BRCA2 requires point-based evidence in the recessive disease context
Still missing
- No BS2 point assignment data were identified.
Sources
BS3 No calibrated benign functional assay result for c.5946del was identified in the reviewed BRCA2 functional evidence sources. BS3 was therefore not assessed. Details ▾Hide ▴
Rule
BS3 requires well-established functional evidence showing no damaging effect
Evidence considered
- No exact c.5946del/Table 9 benign functional match identified
Still missing
- No exact-variant benign functional evidence was identified.
Sources
vcep_specifications_table9_v1_2_2024_11_18
BS4 No quantitative non-segregation likelihood ratio meeting BRCA2 ENIGMA BS4 thresholds was identified for this variant. BS4 was therefore not assessed. Details ▾Hide ▴
Rule
BS4 requires quantitative lack-of-segregation evidence
Evidence considered
- No usable quantitative non-segregation metric identified
Still missing
- No variant-specific lack-of-segregation LR was identified.
Sources
Not applicable · 13· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/AThis criterion is defined for same amino-acid substitutions or equivalent splicing effects relative to a previously classified variant. This variant is a frameshift deletion, so PS1 is not applicable. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PS1 applies to missense or equivalent splicing comparators
Evidence considered
- Variant type is frameshift
Sources
PS2 VCEPDe novo evidence is not part of the applicable BRCA2 ENIGMA framework for this variant assessment, and no validated de novo data were identified. Details ▾Hide ▴
PM1 VCEPPM1 is not applicable in the BRCA2 ENIGMA framework for this truncating variant assessment. Details ▾Hide ▴
PM4 VCEPPM4 is not applicable in the BRCA2 ENIGMA framework for this truncating variant assessment. Details ▾Hide ▴
PM6 VCEPDe novo evidence is not part of the applicable BRCA2 ENIGMA framework for this variant assessment, and no validated de novo data were used here. Details ▾Hide ▴
PP2 VCEPPP2 is not applicable in the BRCA2 ENIGMA framework. Details ▾Hide ▴
PP3 N/AThe BRCA2 ENIGMA PP3 rule is for missense, in-frame, or non-canonical splicing contexts. This variant is a frameshift deletion already evaluated under the truncating-variant framework, so PP3 is not applicable. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PP3 does not apply to this frameshift context
Evidence considered
- Variant type is frameshift
- SpliceAI max delta 0.00
Sources
BP1 N/AThe BRCA2 ENIGMA BP1 rule applies to silent, missense, or in-frame variants outside clinically important domains with no predicted splice effect. This variant is a frameshift deletion, so BP1 is not applicable. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BP1 applies to non-truncating variants only
Evidence considered
- Variant type is frameshift
Sources
BP2 VCEPBP2 is not applicable in the BRCA2 ENIGMA framework. Details ▾Hide ▴
BP3 VCEPBP3 is not applicable in the BRCA2 ENIGMA framework. Details ▾Hide ▴
BP4 N/AThe BRCA2 ENIGMA BP4 rule applies to selected missense, in-frame, silent, or intronic variants with low predicted impact. This variant is a frameshift deletion, so BP4 is not applicable, even though SpliceAI does not predict an additional splice effect (max delta 0.00). Details ▾Hide ▴
Rule
ENIGMA BRCA2 BP4 applies to non-truncating computational contexts
Evidence considered
- Variant type is frameshift
- SpliceAI max delta 0.00
Sources
BP6 VCEPBP6 is not applicable in the BRCA2 ENIGMA framework. Details ▾Hide ▴
BP7 N/AThe BRCA2 ENIGMA BP7 rule applies to silent or intronic variants and selected RNA-only contexts. This variant is a frameshift deletion, so BP7 is not applicable. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BP7 applies to silent/intronic or RNA-only contexts
Evidence considered
- Variant type is frameshift
- SpliceAI max delta 0.00
Sources
Identifiers
- Gene
- BRCA2
- Transcript
- NM_000059.3
- Coding (HGVS c.)
- NM_000059.3:c.5946del
- Protein (HGVS p.)
- NP_000050.2:p.(Ser1982ArgfsTer22)
- GRCh38
- chr13:32340300 GT>G
- GRCh37
- chr13:32914437 GT>G
- ClinVar
- 9325
- COSMIC
- COSV66447676
Gene diagram
Every interpreted variant in BRCA2, mapped onto the exon structure of NM_000059.3. Select a row to find it on the plot.
BRCA2NM_000059.3
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in BRCA2
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
225 / 1,613,878 alleles
AF 0.000139 · 0 homozygotes · FAF 2.15e-05
gnomAD v2.1
78 / 282,088 alleles
AF 0.000277 · 0 homozygotes · FAF 5.39e-05
By genetic ancestry
gnomAD v4.1
AF 0.00014 · 225 / 1,613,878 alleles · 0 hom · FAF 2.2e-05
| Ashkenazi Jewish158 / 29,596 | 0.0053 |
| Remaining individuals31 / 62,478 | 0.0005 |
| European (non-Finnish)35 / 1,179,918 | 3e-05 |
| African/African American1 / 74,912 | 1.3e-05 |
0 alternate alleles recorded in 6 other groups: Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian.
gnomAD v2.1
AF 0.00028 · 78 / 282,088 alleles · 0 hom · FAF 5.4e-05
| Ashkenazi Jewish61 / 10,364 | 0.0059 |
| Remaining individuals3 / 7,180 | 0.00042 |
| European (non-Finnish)14 / 128,890 | 0.00011 |
0 alternate alleles recorded in 5 other groups: African/African American, Admixed American, East Asian, European (Finnish), South Asian.
Statements
gnomAD 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.
gnomAD 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.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 N/AThe BRCA2 ENIGMA PP3 rule is for missense, in-frame, or non-canonical splicing contexts. This variant is a frameshift deletion already evaluated under the truncating-variant framework, so PP3 is not applicable. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PP3 does not apply to this frameshift context
Evidence considered
- Variant type is frameshift
- SpliceAI max delta 0.00
Sources
BP4 N/AThe BRCA2 ENIGMA BP4 rule applies to selected missense, in-frame, silent, or intronic variants with low predicted impact. This variant is a frameshift deletion, so BP4 is not applicable, even though SpliceAI does not predict an additional splice effect (max delta 0.00). Details ▾Hide ▴
Rule
ENIGMA BRCA2 BP4 applies to non-truncating computational contexts
Evidence considered
- Variant type is frameshift
- SpliceAI max delta 0.00
Sources
BP7 N/AThe BRCA2 ENIGMA BP7 rule applies to silent or intronic variants and selected RNA-only contexts. This variant is a frameshift deletion, so BP7 is not applicable. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BP7 applies to silent/intronic or RNA-only contexts
Evidence considered
- Variant type is frameshift
- SpliceAI max delta 0.00
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
9 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
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PMID 10570174 ↗Truncated BRCA2 is cytoplasmic: implications for cancer-linked mutations.No paper-specific finding is recorded.
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PMID 11239455 ↗BRCA2 is required for homology-directed repair of chromosomal breaks.No paper-specific finding is recorded.
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PMID 20878484 ↗A new mutation of BRCA2 gene in an Italian healthy woman with familial breast cancer history.No paper-specific finding is recorded.
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PMID 22193408 ↗BRCA1 and BRCA2: different roles in a common pathway of genome protection.No paper-specific finding is recorded.
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PMID 24312913 ↗A comprehensive focus on global spectrum of BRCA1 and BRCA2 mutations in breast cancer.No paper-specific finding is recorded.
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PMID 10417300 ↗De novo BRCA1 mutation in a patient with breast cancer and an inherited BRCA2 mutation.Tesoriero A et al. · 1999No paper-specific finding is recorded.
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PMID 14559878 ↗Shared genetic susceptibility to breast cancer, brain tumors, and Fanconi anemia.Offit K et al. · 2003No paper-specific finding is recorded.
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PMID 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.No paper-specific finding is recorded.
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
225 / 1,613,878 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
67 Pathogenic · 1 pathogenic
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
ClinGen CSpec
Captured ClinGen CSpec source record
Open source ↗
All source links
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/1535438831
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/9325/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/13-32914437-GT-G?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr13-32340300-GT-G?dataset=g…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000059.3%3Ac.5946…
- OncoKB ↗www.oncokb.org/gene/BRCA2/S1982Rfs*22
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=123597301
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD 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.
gnomAD 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.
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
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV66447676, n = 10 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.