About BRCA2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRCA2 c.8375T>C, p.(Leu2792Pro)
Classification
Likely pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.
Likely pathogenic.A likely 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: 3
Benign evidence criteria: 0
Pathogenic criteria applied · 3
PS3Strong
PS3 · strong
In the ENIGMA BRCA2 functional assay table, this exact variant, c.8375T>C (p.Leu2792Pro), is reported by two calibrated studies to show damaging protein function, and the table assigns PS3 at strong strength.
PP3Supporting
PP3 · supporting
This missense variant lies within the BRCA2 DNA-binding domain, a clinically important functional domain defined by ENIGMA (amino acids 2481-3186). BayesDel is 0.54225, which is above the ENIGMA PP3 threshold of 0.30, and REVEL is also high at 0.931. SpliceAI predicts no significant splice effect (max delta 0.03), so the computational evidence supports a damaging protein effect rather than a splice mechanism.
PP5Supporting
PP5 · supporting
Expert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Likely pathogenic.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Likely pathogenic
ENIGMA BRCA1 and BRCA2 Specification v1.2 official final-classification framework was used, applying the Table 3 criteria-combination rules captured in 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
1 / 1,613,924 alleles
gnomAD v4.1: 1 / 1,613,924 alleles. Recorded AF 6.19608e-07. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
No listed criterion applied
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
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.
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: 3 met · 8 not met · 7 not assessed · 10 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.8375T>C (p.Leu2792Pro) variant has been reported in ClinVar, including a Likely Pathogenic expert-panel classification from ClinGen ENIGMA.
This variant is absent from gnomAD v2.1 and is present once in gnomAD v4.1 (1/1613924 alleles; AF 6.19608e-07), supporting rarity but not strict absence across available population datasets.
In the ENIGMA BRCA2 curated functional dataset, two calibrated studies showed damaging protein function for this exact variant, and Table 9 assigns PS3 at strong strength.
In silico data support a damaging protein effect within the BRCA2 DNA-binding domain, with BayesDel 0.54225 and REVEL 0.931, while SpliceAI predicts no significant splice impact (max delta 0.03).
No criteria match.
Met · 3
PS3 StrongIn the ENIGMA BRCA2 functional assay table, this exact variant, c.8375T>C (p.Leu2792Pro), is reported by two calibrated studies to show damaging protein function, and the table assigns PS3 at strong strength. Details ▾Hide ▴
Rule
ENIGMA BRCA2 Table 9 assigns PS3/BS3 strengths from calibrated published functional assays.
Evidence considered
- ENIGMA Table 9 exact-variant row for c.8375T>C / p.(Leu2792Pro)
- Assigned code PS3 Strong
- Two calibrated studies reported damaging function
Sources
PP3 SupportingThis missense variant lies within the BRCA2 DNA-binding domain, a clinically important functional domain defined by ENIGMA (amino acids 2481-3186). BayesDel is 0.54225, which is above the ENIGMA PP3 threshold of 0.30, and REVEL is also high at 0.931. SpliceAI predicts no significant splice effect (max delta 0.03), so the computational evidence supports a damaging protein effect rather than a splice mechanism. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PP3 applies to missense variants in a clinically important domain with BayesDel no-AF score >=0.30.
Evidence considered
- Protein position 2792 lies within BRCA2 DNA-binding domain
- BayesDel 0.54225
- REVEL 0.931
- SpliceAI max delta 0.03
Sources
PP5 SupportingExpert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Likely pathogenic. Details ▾Hide ▴
Not met · 8 · evaluated, threshold not reached
PVS1 This variant is a missense substitution, p.(Leu2792Pro), and does not fall into the BRCA2 null-variant or canonical splice categories used for PVS1. SpliceAI predicts no significant splice effect (max delta score 0.03), so available evidence does not support applying PVS1. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PVS1 applies to null variants or qualifying RNA evidence; neither is established here.
Evidence considered
- Missense consequence p.(Leu2792Pro)
- Generic PVS1 scaffold indicates variant is outside default null-variant buckets
- SpliceAI max delta 0.03
Sources
PS1 No distinct previously classified pathogenic or likely pathogenic variant producing the same amino acid change was identified in the available ClinVar evidence, so PS1 is not established. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PS1 requires a previously classified variant with the same protein or splice consequence.
Evidence considered
- ClinVar variation record reviewed for this amino acid change
Still missing
- A broader amino-acid-level search across additional curated databases could be performed if needed.
Sources
PM2 This variant is absent from gnomAD v2.1, but it is present in gnomAD v4.1 at 1/1613924 alleles (AF 6.19608e-07; highest population AF 8.47529e-07 in European non-Finnish). Available population data therefore support rarity, but do not establish the strict absence required for ENIGMA PM2. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PM2 applies only when the variant is absent from specified control datasets.
Evidence considered
- gnomAD v2.1 absent
- gnomAD v4.1 total AC 1/AN 1613924
- Highest observed population AF 8.47529e-07
Still missing
- The ENIGMA rule is defined against absence in specified gnomAD reference datasets
- strict absence is not demonstrated from available data.
Sources
BA1 Available population data do not meet the ENIGMA BA1 threshold. The observed gnomAD v4.1 frequency is 6.19608e-07, which is far below the BA1 threshold of greater than 0.001. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BA1 requires filter allele frequency >0.001.
Evidence considered
- gnomAD v4.1 total AF 6.19608e-07
Sources
BS1 Available population data do not meet the ENIGMA BS1 thresholds. The observed gnomAD v4.1 frequency is 6.19608e-07, which is below the supporting threshold of greater than 0.00002 and far below the strong threshold of greater than 0.0001. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BS1 requires filter allele frequency above defined benign thresholds.
Evidence considered
- gnomAD v4.1 total AF 6.19608e-07
Sources
BS3 Available functional evidence does not support a benign effect. Instead, the ENIGMA BRCA2 functional assay table reports that two calibrated studies showed damaging protein function for this exact variant and assigns PS3_Strong. Details ▾Hide ▴
Rule
BS3 applies only when well-established functional studies show no damaging effect.
Evidence considered
- ENIGMA Table 9 exact-variant row assigns PS3 Strong
- Damaging functional results reported in two calibrated studies
Sources
BP1 BP1_Strong is reserved for missense or silent variants outside clinically important BRCA2 domains with no predicted splice effect. This variant is within the BRCA2 DNA-binding domain, so BP1 is not met. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BP1 applies only outside clinically important domains.
Evidence considered
- Protein position 2792 lies within BRCA2 DNA-binding domain
- SpliceAI max delta 0.03
Sources
BP4 This variant is within the BRCA2 DNA-binding domain, but the computational results do not meet the benign thresholds. BayesDel is 0.54225, which is above the BP4 threshold of 0.18, although SpliceAI is low at 0.03. Available in silico evidence therefore does not support BP4. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BP4 requires BayesDel <=0.18 and SpliceAI <=0.1 for an eligible missense variant in domain.
Evidence considered
- Protein position 2792 lies within BRCA2 DNA-binding domain
- BayesDel 0.54225
- SpliceAI max delta 0.03
Sources
Not assessed · 7 · no assessment recorded
PS4 No case-control analysis or other evidence showing statistically significant enrichment in affected individuals was identified for this variant, and no exact-variant entry was identified in the reviewed BRCA2 multifactorial/posterior tables for PS4 use. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PS4 requires significant enrichment in affected individuals versus controls.
Evidence considered
- Exact-variant lookup in Supplementary Table 7 did not identify c.8375T>C / p.(Leu2792Pro)
- Exact-variant lookup in Parsons 2019 multifactorial table did not identify c.8375T>C / p.(Leu2792Pro)
Still missing
- Case-control or multifactorial enrichment data specific to this variant were not identified.
Sources
PM3 No evidence was identified showing this variant in trans with another BRCA2 pathogenic variant in an individual with a phenotype consistent with BRCA2-related Fanconi anemia, so PM3 cannot be assessed. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PM3 is restricted to Fanconi anemia-related biallelic observations.
Evidence considered
- BRCA2 ENIGMA PM3 rule reviewed
Still missing
- No phase data or Fanconi anemia phenotype data were identified.
Sources
PP1 No quantitative co-segregation data were identified for this variant, and no exact-variant segregation likelihood ratio was identified in the reviewed BRCA2 multifactorial resources, so PP1 cannot be applied. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PP1 requires quantitative co-segregation evidence.
Evidence considered
- Exact-variant lookup in Parsons 2019 multifactorial table did not identify c.8375T>C / p.(Leu2792Pro)
Still missing
- No informative family segregation likelihood ratio was identified.
Sources
vcep_humu_40_1557_s001cspec ↗
PP4 No exact-variant personal or family-history likelihood ratio was identified in the reviewed BRCA2 clinical-history table, so PP4 cannot be applied from the available multifactorial clinical data. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PP4 requires a variant-specific multifactorial clinical likelihood ratio meeting threshold.
Evidence considered
- Exact-variant lookup in BRCA2 clinical-history LR table did not identify c.8375T>C
Still missing
- No exact clinical-history likelihood ratio was identified for this variant.
Sources
BS2 No evidence was identified showing this variant in individuals without features of BRCA2-related Fanconi anemia in a way that permits ENIGMA BS2 point assignment. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BS2 requires point-based evidence in individuals without Fanconi anemia features.
Evidence considered
- BRCA2 ENIGMA BS2 rule reviewed
Still missing
- No BS2 point-based proband data were identified.
Sources
BS4 No quantitative lack-of-segregation data were identified for this variant, and no exact-variant segregation likelihood ratio was identified in the reviewed BRCA2 multifactorial resources, so BS4 cannot be applied. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BS4 requires quantitative evidence for lack of segregation.
Evidence considered
- Exact-variant lookup in Parsons 2019 multifactorial table did not identify c.8375T>C / p.(Leu2792Pro)
Still missing
- No informative non-segregation likelihood ratio was identified.
Sources
vcep_humu_40_1557_s001cspec ↗
BP5 No exact-variant personal or family-history likelihood ratio was identified in the reviewed BRCA2 clinical-history table, so BP5 cannot be applied from the available multifactorial clinical data. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BP5 requires a variant-specific multifactorial clinical likelihood ratio meeting benign thresholds.
Evidence considered
- Exact-variant lookup in BRCA2 clinical-history LR table did not identify c.8375T>C
Still missing
- No exact clinical-history likelihood ratio was identified for this variant.
Sources
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PS2 N/AThis criterion is marked not applicable in the BRCA2 ENIGMA specification. Details ▾Hide ▴
Rule
Not applicable in this framework.
Evidence considered
- BRCA2 ENIGMA specification applicability
Sources
PM1 N/AThis criterion is marked not applicable in the BRCA2 ENIGMA specification. Details ▾Hide ▴
Rule
Not applicable in this framework.
Evidence considered
- BRCA2 ENIGMA specification applicability
Sources
PM4 N/AThis criterion is marked not applicable in the BRCA2 ENIGMA specification. Details ▾Hide ▴
Rule
Not applicable in this framework.
Evidence considered
- BRCA2 ENIGMA specification applicability
Sources
PM5 N/AIn the BRCA2 ENIGMA specification, PM5 is defined here for protein-terminating variants in eligible exons. This missense variant does not meet that use case. Details ▾Hide ▴
Rule
BRCA2 ENIGMA PM5 in this framework applies to PTC variants, not this missense change.
Evidence considered
- BRCA2 ENIGMA PM5 rule is PTC-specific in this framework
Sources
cspec ↗vcep_specifications_table4_v1_2_2024_11_18
PM6 N/AThis criterion is marked not applicable in the BRCA2 ENIGMA specification. Details ▾Hide ▴
Rule
Not applicable in this framework.
Evidence considered
- BRCA2 ENIGMA specification applicability
Sources
PP2 N/AThis criterion is marked not applicable in the BRCA2 ENIGMA specification. Details ▾Hide ▴
Rule
Not applicable in this framework.
Evidence considered
- BRCA2 ENIGMA specification applicability
Sources
BP2 N/AThis criterion is marked not applicable in the BRCA2 ENIGMA specification. Details ▾Hide ▴
Rule
Not applicable in this framework.
Evidence considered
- BRCA2 ENIGMA specification applicability
Sources
BP3 N/AThis criterion is marked not applicable in the BRCA2 ENIGMA specification. Details ▾Hide ▴
Rule
Not applicable in this framework.
Evidence considered
- BRCA2 ENIGMA specification applicability
Sources
BP6 N/AThis criterion is marked not applicable in the BRCA2 ENIGMA specification. Details ▾Hide ▴
Rule
Not applicable in this framework.
Evidence considered
- BRCA2 ENIGMA specification applicability
Sources
BP7 N/ABP7 in this framework is for silent or qualifying intronic variants, and this is a missense variant within a clinically important BRCA2 domain. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BP7 does not apply to this missense variant in domain.
Evidence considered
- Missense consequence p.(Leu2792Pro)
- Protein position 2792 lies within BRCA2 DNA-binding domain
- SpliceAI max delta 0.03
Sources
Identifiers
- Gene
- BRCA2
- Transcript
- NM_000059.3
- Coding (HGVS c.)
- NM_000059.3:c.8375T>C
- Protein (HGVS p.)
- NP_000050.2:p.(Leu2792Pro)
- GRCh38
- chr13:32370445 T>C
- GRCh37
- chr13:32944582 T>C
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
1 / 1,613,924 alleles
AF 6.2e-07 · 0 homozygotes
gnomAD v2.1
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 6.2e-07 · 1 / 1,613,924 alleles · 0 hom
| European (non-Finnish)1 / 1,179,900 | 8.5e-07 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 6.19608e-07; MAF= 0.00006%, 1/1613924 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47529e-07; MAF= 0.00008%, 1/1179900 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 SupportingThis missense variant lies within the BRCA2 DNA-binding domain, a clinically important functional domain defined by ENIGMA (amino acids 2481-3186). BayesDel is 0.54225, which is above the ENIGMA PP3 threshold of 0.30, and REVEL is also high at 0.931. SpliceAI predicts no significant splice effect (max delta 0.03), so the computational evidence supports a damaging protein effect rather than a splice mechanism. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PP3 applies to missense variants in a clinically important domain with BayesDel no-AF score >=0.30.
Evidence considered
- Protein position 2792 lies within BRCA2 DNA-binding domain
- BayesDel 0.54225
- REVEL 0.931
- SpliceAI max delta 0.03
Sources
BP4 This variant is within the BRCA2 DNA-binding domain, but the computational results do not meet the benign thresholds. BayesDel is 0.54225, which is above the BP4 threshold of 0.18, although SpliceAI is low at 0.03. Available in silico evidence therefore does not support BP4. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BP4 requires BayesDel <=0.18 and SpliceAI <=0.1 for an eligible missense variant in domain.
Evidence considered
- Protein position 2792 lies within BRCA2 DNA-binding domain
- BayesDel 0.54225
- SpliceAI max delta 0.03
Sources
BP7 N/ABP7 in this framework is for silent or qualifying intronic variants, and this is a missense variant within a clinically important BRCA2 domain. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BP7 does not apply to this missense variant in domain.
Evidence considered
- Missense consequence p.(Leu2792Pro)
- Protein position 2792 lies within BRCA2 DNA-binding domain
- SpliceAI max delta 0.03
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.931. BayesDel score = 0.54225.
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
1 / 1,613,924 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/52568/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/13-32944582-T-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr13-32370445-T-C?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000059.3%3Ac.8375…
- OncoKB ↗www.oncokb.org/gene/BRCA2/L2792P
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=BRCA2+c.8375T%3EC
- 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= 6.19608e-07; MAF= 0.00006%, 1/1613924 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47529e-07; MAF= 0.00008%, 1/1179900 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant has been reported in ClinVar as Likely pathogenic (3 clinical laboratories) and as Uncertain significance (2 clinical laboratories) and as Likely Pathogenic 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 = 0.03). REVEL score = 0.931. BayesDel score = 0.54225.
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 not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.