About BRCA2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRCA2 c.9976A>T, p.(Lys3326Ter)
Classification
Benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is benign. Select a step to read what it means.
Benign.A benign 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: 0
Benign evidence criteria: 4
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 4
BA1Stand alone
BA1 · stand alone
This variant is common in population databases. In gnomAD v2.1, grpmax FAF is 0.00849119 (0.849119%), which is above the BRCA2 ENIGMA BA1 threshold of 0.001 (0.1%); the overall allele frequency is 0.00646801 (0.64680%), and gnomAD v4.1 also shows an overall allele frequency of 0.00791559 (0.79156%).
BS1Strong
BS1 · strong
The population frequency is also above the BRCA2 ENIGMA BS1 threshold. In gnomAD v2.1, grpmax FAF is 0.00849119 (0.849119%), which is above the BS1 Strong threshold of 0.0001 (0.01%).
BS3Strong
BS3 · strong
Calibrated functional evidence in the BRCA2 expert specification supports a benign effect. This exact variant is listed as BS3 Strong, with protein function similar to benign control variants; SpliceAI also predicts no significant splice impact (max delta score 0.07).
BP6Supporting
BP6 · supporting
Expert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Benign.
Recorded classification: Benign
ClinGen ENIGMA BRCA1/BRCA2 Specification v1.2.0 Table 3 final-classification framework (CSPEC/VCEP primary authority)
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
12,777 / 1,614,156 alleles
gnomAD v4.1: 12,777 / 1,614,156 alleles. Recorded AF 0.00791559. Recorded homozygote count 72.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.00646801; MAF= 0.64680%, 1825/282158 alleles, homozygotes = 14) and has highest observed frequency in the European (Finnish) population (AF= 0.0109111; MAF= 1.09111%, 274/25112 alleles, homozygotes = 2); grpmax FAF= 0.00849119.
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
No listed criterion applied
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Functional evidence
Statement recorded
OncoKB classifies this variant as Inconclusive; biological effect: Inconclusive.
COSMIC
Cancer Hotspots
Somatic evidence
Not assessed
No COSMIC evidence statement is recorded in this case.
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 · 3 not met · 7 not assessed · 14 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.9976A>T (p.Lys3326Ter, K3326*) variant has been observed in somatic cancers in COSMIC (18 occurrences) and has been reported in ClinVar with an expert-panel benign classification.
This variant is common in population databases, including gnomAD v2.1 with an overall allele frequency of 0.64680% and grpmax FAF of 0.849119%, and gnomAD v4.1 with an overall allele frequency of 0.79156%; these values are above the BRCA2 ENIGMA BA1 (>0.1%) and BS1 (>0.01%) thresholds.
Calibrated BRCA2 functional evidence supports a benign effect, with the expert specification assigning BS3 Strong to this exact variant based on protein function similar to benign controls.
SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.07.
No criteria match.
Met · 4
BA1 Stand aloneThis variant is common in population databases. In gnomAD v2.1, grpmax FAF is 0.00849119 (0.849119%), which is above the BRCA2 ENIGMA BA1 threshold of 0.001 (0.1%); the overall allele frequency is 0.00646801 (0.64680%), and gnomAD v4.1 also shows an overall allele frequency of 0.00791559 (0.79156%). Details ▾Hide ▴
Rule
BRCA2 ENIGMA BA1: FAF >0.001 in gnomAD
Evidence considered
- gnomAD v2.1 grpmax FAF 0.00849119 > BA1 threshold 0.001
- gnomAD v2.1 total AF 0.00646801
- 1825/282158 alleles
- 14 homozygotes
- gnomAD v4.1 total AF 0.00791559
- 12777/1614156 alleles
- 72 homozygotes
Sources
BS1 StrongThe population frequency is also above the BRCA2 ENIGMA BS1 threshold. In gnomAD v2.1, grpmax FAF is 0.00849119 (0.849119%), which is above the BS1 Strong threshold of 0.0001 (0.01%). Details ▾Hide ▴
Rule
BRCA2 ENIGMA BS1 Strong: FAF >0.0001 in gnomAD
Evidence considered
- gnomAD v2.1 grpmax FAF 0.00849119 > BS1 Strong threshold 0.0001
- gnomAD v4.1 grpmax FAF 0.00883986
Sources
BS3 StrongCalibrated functional evidence in the BRCA2 expert specification supports a benign effect. This exact variant is listed as BS3 Strong, with protein function similar to benign control variants; SpliceAI also predicts no significant splice impact (max delta score 0.07). Details ▾Hide ▴
Rule
BRCA2 ENIGMA BS3 Strong from calibrated functional study evidence
Evidence considered
- ENIGMA Table 9 exact-variant entry assigns BS3 Strong
- Table 9 notes protein function similar to benign controls
- SpliceAI max delta score 0.07
Sources
Not met · 3 · evaluated, threshold not reached
PS3 Available functional evidence does not support a damaging effect. The BRCA2 expert specification lists this exact variant as BS3 Strong, reporting protein function similar to benign control variants, so PS3 is not met. Details ▾Hide ▴
Rule
PS3 requires well-established studies showing a damaging effect
Evidence considered
- ENIGMA Table 9 exact-variant entry: c.9976A>T p.(Lys3326Ter) = BS3 Strong
- Table 9 notes protein function similar to benign controls
Sources
cspec ↗vcep_specifications_table9_v1_2_2024_11_18
PS4 Available evidence does not show the marked enrichment in affected individuals required for PS4. The retrieved BRCA2 expert materials did not identify qualifying case-control evidence for pathogenic enrichment of this variant, and the reference-set materials list it as likely benign rather than supporting increased prevalence in affected individuals. Details ▾Hide ▴
Rule
BRCA2 ENIGMA PS4 requires significant enrichment in affected individuals
Evidence considered
- No qualifying ENIGMA PS4 case-control evidence identified
- Supplementary Table 7 lists c.9976A>T as (Likely) Benign
Still missing
- Qualifying case-control data with p-value ≤0.05 and OR ≥4 for the relevant BRCA2-associated disease context
Sources
PM2 This variant is not absent from population databases. In gnomAD v2.1, the overall allele frequency is 0.00646801 (0.64680%) with grpmax FAF 0.00849119, which is far above the PM2 requirement for absence from controls. Details ▾Hide ▴
Rule
BRCA2 ENIGMA PM2 requires absence from controls
Evidence considered
- gnomAD v2.1 total AF 0.00646801
- 1825/282158 alleles
- 14 homozygotes
- gnomAD v2.1 grpmax FAF 0.00849119
- gnomAD v4.1 total AF 0.00791559
- 12777/1614156 alleles
- 72 homozygotes
Sources
Not assessed · 7 · no assessment recorded
PS2 No confirmed de novo data with parental relationships and phenotypic specificity were identified, so PS2 was not assessed. Details ▾Hide ▴
Evidence considered
- No de novo evidence was identified in the retrieved materials
Still missing
- Documented maternity and paternity with confirmed de novo occurrence
Sources
PM3 No evidence was identified for this variant in trans with another BRCA2 variant in a phenotype consistent with BRCA2-related Fanconi anemia, so PM3 was not assessed. Details ▾Hide ▴
Evidence considered
- No PM3-qualifying recessive disease evidence identified
Still missing
- Confirmed trans observations in BRCA2-related Fanconi anemia with sufficient point total
Sources
PP1 No quantitative co-segregation data were identified for this variant, so PP1 was not assessed. Details ▾Hide ▴
Evidence considered
- No variant-specific quantitative segregation LR was identified in the retrieved materials
Still missing
- Segregation likelihood ratio meeting ENIGMA PP1 thresholds
Sources
PP4 No qualifying multifactorial clinical likelihood ratio supporting pathogenicity was identified for this variant, so PP4 was not assessed. Details ▾Hide ▴
Evidence considered
- No qualifying PP4 LR was identified in the retrieved structured BRCA2 materials
Still missing
- Variant-specific clinical-history or combined multifactorial LR ≥2.08
Sources
BS2 No point-based evidence in unaffected individuals without features of BRCA2-related Fanconi anemia was identified, so BS2 was not assessed. Details ▾Hide ▴
Evidence considered
- No BS2-qualifying unaffected-observation dataset was identified
Still missing
- BS2 point-based unaffected observations meeting ENIGMA thresholds
Sources
BS4 No quantitative lack-of-segregation likelihood ratio was identified for this variant, so BS4 was not assessed. Details ▾Hide ▴
Evidence considered
- No variant-specific BS4 segregation LR was identified in the retrieved materials
Still missing
- Segregation likelihood ratio ≤0.48
- ≤0.23
- or ≤0.05 for BS4 strength assignment
Sources
BP5 No qualifying multifactorial clinical likelihood ratio against pathogenicity was identified in the retrieved structured BRCA2 materials, so BP5 was not assessed. Details ▾Hide ▴
Evidence considered
- No qualifying BP5 LR was identified in the retrieved structured BRCA2 materials
Still missing
- Variant-specific clinical-history or combined multifactorial LR ≤0.48
Sources
Not applicable · 14· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis nonsense variant occurs in BRCA2 exon 27, but the BRCA2 expert specification marks protein-termination variants in exon 27 after p.Glu3309 as PVS1_N/A. p.Lys3326Ter lies beyond this cutoff, so loss-of-function evidence is not counted under PVS1 for this variant. Details ▾Hide ▴
Rule
BRCA2 ENIGMA Table 4: exon 27 PTC variants after p.Glu3309 are PVS1_N/A
Evidence considered
- BRCA2 exon 27 Table 4 row: PTC>p.E3309 is annotated PVS1_N/A
- Variant protein consequence is p.(Lys3326Ter)
- which is distal to p.Glu3309
Sources
cspec ↗vcep_specifications_table4_v1_2_2024_11_18
PS1 N/APS1 is defined in this specification for predicted missense substitutions or variants with the same predicted splice effect as a previously classified pathogenic variant. This variant is a nonsense change, so PS1 is not applicable. Details ▾Hide ▴
Rule
BRCA2 ENIGMA PS1 applies to missense or splice-equivalent variants
Evidence considered
- BRCA2 ENIGMA PS1 rule is limited to missense or splice-equivalent variants
- Variant consequence is p.(Lys3326Ter)
Sources
PM1 N/APM1 is not applicable in the BRCA2 expert specification for this variant type. This variant is a distal nonsense change and is not being evaluated as a missense variant within a clinically important functional domain. Details ▾Hide ▴
Rule
PM1 not applicable for this variant in BRCA2 specification
Evidence considered
- BRCA2 ENIGMA marks PM1 as not applicable here
- Variant is p.(Lys3326Ter)
- not a missense change
Sources
PM4 N/APM4 is not applicable in this BRCA2 expert framework for this variant. Details ▾Hide ▴
Rule
PM4 not applicable
Evidence considered
- BRCA2 ENIGMA marks PM4 as not applicable here
Sources
PM5 N/AThe BRCA2 expert specification excludes PM5_PTC for exon 27 protein-termination variants after p.Glu3309. Because p.Lys3326Ter is beyond this cutoff, PM5 is not applicable. Details ▾Hide ▴
Rule
BRCA2 ENIGMA Table 4: exon 27 PTC variants after p.Glu3309 are PM5_N/A
Evidence considered
- BRCA2 exon 27 Table 4 row: PTC>p.E3309 is annotated PM5_N/A
- Variant protein consequence is p.(Lys3326Ter)
Sources
cspec ↗vcep_specifications_table4_v1_2_2024_11_18
PM6 N/APM6 is marked not applicable in this BRCA2 expert specification. Details ▾Hide ▴
PP2 N/APP2 is marked not applicable in this BRCA2 expert specification. Details ▾Hide ▴
PP3 N/APP3 in the BRCA2 expert specification is used for missense, in-frame, or non-canonical splice-relevant variants. This variant is a nonsense change, and SpliceAI does not predict significant splice disruption (max delta score 0.07), so PP3 is not applicable. Details ▾Hide ▴
Rule
BRCA2 ENIGMA PP3 applies to missense/in-frame or predicted splicing variants
Evidence considered
- Variant consequence is p.(Lys3326Ter)
- SpliceAI max delta score 0.07
Sources
PP5 N/APP5 is marked not applicable in this BRCA2 expert specification. Details ▾Hide ▴
BP1 N/ABP1 in the BRCA2 expert specification is used for silent, missense, or in-frame variants outside clinically important functional domains with no splice effect. This variant is a nonsense change, so BP1 is not applicable. Details ▾Hide ▴
Rule
BRCA2 ENIGMA BP1 applies to silent/missense/in-frame variants
Evidence considered
- Variant consequence is p.(Lys3326Ter)
- BP1 rule does not apply to nonsense variants
Sources
BP2 N/ABP2 is marked not applicable in this BRCA2 expert specification. Details ▾Hide ▴
BP3 N/ABP3 is marked not applicable in this BRCA2 expert specification. Details ▾Hide ▴
BP4 N/ASpliceAI predicts no significant splice impact for this variant (max delta score 0.07), but BP4 in the BRCA2 expert specification is defined for missense, in-frame, silent, or eligible intronic variants. This nonsense variant is not eligible for BP4. Details ▾Hide ▴
Rule
BRCA2 ENIGMA BP4 applies to missense/in-frame/silent/intronic variants
Evidence considered
- SpliceAI max delta score 0.07
- BP4 rule does not include nonsense variants
Sources
BP7 N/ABP7 in the BRCA2 expert specification is defined for silent or intronic variants, and in some RNA-only scenarios for missense or in-frame variants outside key domains. This nonsense variant is not eligible for BP7. Details ▾Hide ▴
Rule
BRCA2 ENIGMA BP7 applies to silent/intronic or specified RNA-only scenarios, not nonsense variants
Evidence considered
- Variant consequence is p.(Lys3326Ter)
- SpliceAI max delta score 0.07
Sources
Identifiers
- Gene
- BRCA2
- Transcript
- NM_000059.4
- Coding (HGVS c.)
- NM_000059.4:c.9976A>T
- Protein (HGVS p.)
- NP_000050.3:p.(Lys3326Ter)
- GRCh38
- chr13:32398489 A>T
- GRCh37
- chr13:32972626 A>T
Gene diagram
Every interpreted variant in BRCA2, mapped onto the exon structure of NM_000059.4. Select a row to find it on the plot.
BRCA2NM_000059.4
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
12,777 / 1,614,156 alleles
AF 0.00792 · 72 homozygotes · FAF 0.00884
gnomAD v2.1
1,825 / 282,158 alleles
AF 0.00647 · 14 homozygotes · FAF 0.00849
By genetic ancestry
gnomAD v4.1
AF 0.0079 · 12777 / 1,614,156 alleles · 72 hom · FAF 0.0088
| Amish32 / 910 | 0.0352 hom |
| European (Finnish)637 / 64,034 | 0.00995 hom |
| European (non-Finnish)10600 / 1,180,014 | 0.00951 hom |
| Remaining individuals451 / 62,504 | 0.00721 hom |
| Middle Eastern42 / 6,062 | 0.00691 hom |
| South Asian594 / 91,086 | 0.006511 hom |
| Ashkenazi Jewish136 / 29,604 | 0.0046 |
| Admixed American197 / 60,008 | 0.00331 hom |
| African/African American88 / 75,044 | 0.0012 |
0 alternate alleles recorded in 1 other group: East Asian.
gnomAD v2.1
AF 0.0065 · 1825 / 282,158 alleles · 14 hom · FAF 0.0085
| European (Finnish)274 / 25,112 | 0.0112 hom |
| European (non-Finnish)1124 / 128,854 | 0.00876 hom |
| South Asian212 / 30,594 | 0.00695 hom |
| Remaining individuals46 / 7,190 | 0.00641 hom |
| Ashkenazi Jewish42 / 10,358 | 0.0041 |
| Admixed American94 / 35,348 | 0.0027 |
| African/African American33 / 24,778 | 0.0013 |
0 alternate alleles recorded in 1 other group: East Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.00791559; MAF= 0.79156%, 12777/1614156 alleles, homozygotes = 72) and has highest observed frequency in the Amish population (AF= 0.0351648; MAF= 3.51648%, 32/910 alleles, homozygotes = 2); grpmax FAF= 0.00883986.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.00646801; MAF= 0.64680%, 1825/282158 alleles, homozygotes = 14) and has highest observed frequency in the European (Finnish) population (AF= 0.0109111; MAF= 1.09111%, 274/25112 alleles, homozygotes = 2); grpmax FAF= 0.00849119.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 N/APP3 in the BRCA2 expert specification is used for missense, in-frame, or non-canonical splice-relevant variants. This variant is a nonsense change, and SpliceAI does not predict significant splice disruption (max delta score 0.07), so PP3 is not applicable. Details ▾Hide ▴
Rule
BRCA2 ENIGMA PP3 applies to missense/in-frame or predicted splicing variants
Evidence considered
- Variant consequence is p.(Lys3326Ter)
- SpliceAI max delta score 0.07
Sources
BP4 N/ASpliceAI predicts no significant splice impact for this variant (max delta score 0.07), but BP4 in the BRCA2 expert specification is defined for missense, in-frame, silent, or eligible intronic variants. This nonsense variant is not eligible for BP4. Details ▾Hide ▴
Rule
BRCA2 ENIGMA BP4 applies to missense/in-frame/silent/intronic variants
Evidence considered
- SpliceAI max delta score 0.07
- BP4 rule does not include nonsense variants
Sources
BP7 N/ABP7 in the BRCA2 expert specification is defined for silent or intronic variants, and in some RNA-only scenarios for missense or in-frame variants outside key domains. This nonsense variant is not eligible for BP7. Details ▾Hide ▴
Rule
BRCA2 ENIGMA BP7 applies to silent/intronic or specified RNA-only scenarios, not nonsense variants
Evidence considered
- Variant consequence is p.(Lys3326Ter)
- SpliceAI max delta score 0.07
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07).
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
12,777 / 1,614,156 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Captured SpliceAI source record
Open source ↗
ClinVar
Captured ClinVar source record
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/38266/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/13-32972626-A-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr13-32398489-A-T?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000059.4%3Ac.9976…
- OncoKB ↗www.oncokb.org/gene/BRCA2/K3326*
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=123597627
- 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= 0.00791559; MAF= 0.79156%, 12777/1614156 alleles, homozygotes = 72) and has highest observed frequency in the Amish population (AF= 0.0351648; MAF= 3.51648%, 32/910 alleles, homozygotes = 2); grpmax FAF= 0.00883986.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.00646801; MAF= 0.64680%, 1825/282158 alleles, homozygotes = 14) and has highest observed frequency in the European (Finnish) population (AF= 0.0109111; MAF= 1.09111%, 274/25112 alleles, homozygotes = 2); grpmax FAF= 0.00849119.
ClinVar
This variant has been reported in ClinVar as Benign (30 clinical laboratories) and as Likely benign (10 clinical laboratories) and as Uncertain significance (1 clinical laboratory) and as Benign by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07).
Functional
OncoKB classifies this variant as Inconclusive; biological effect: Inconclusive.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV66337127, n = 18 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.