About BRCA2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRCA2 c.7961T>C, p.(Leu2654Pro)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
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: 1
Benign evidence criteria: 0
Pathogenic criteria applied · 1
PP3Supporting
PP3 · supporting
This missense variant lies within the BRCA2 DNA-binding domain (aa 2481-3186). BayesDel no-AF is 0.314702, which is above the ENIGMA PP3 threshold of ≥0.30, REVEL is 0.82, and SpliceAI predicts no significant splice effect (max delta 0.02), supporting a damaging protein effect; therefore PP3 is met at supporting strength.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
ENIGMA BRCA1 and BRCA2 Specification v1.2 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
3 / 1,614,066 alleles
gnomAD v4.1: 3 / 1,614,066 alleles. Recorded AF 1.85866e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.1841e-05; MAF= 0.00318%, 1/31406 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000114784; MAF= 0.01148%, 1/8712 alleles, homozygotes = 0).
No listed criterion applied
SpliceAI score
0.020 maximum delta
Recorded SpliceAI maximum delta score: 0.020. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
5 reported laboratory submissions
3 Uncertain significance · 1 Uncertain Significance · 1 Likely pathogenic.
Context only
ClinVar ↗
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
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
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: 1 met · 10 not met · 6 not assessed · 11 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.7961T>C (p.Leu2654Pro) variant has been reported in ClinVar with an expert-panel classification of uncertain significance and mixed submitter assertions.
This variant is present at very low frequency in population databases, including 1/31,406 alleles in gnomAD v2.1 and 3/1,614,066 alleles in gnomAD v4.1, which argues against PM2 and does not reach BA1 or BS1 thresholds.
In the ENIGMA BRCA2 curated functional dataset, this variant has discordant calibrated assay results, so the available functional evidence does not support either PS3 or BS3.
Computational evidence supports a damaging protein effect because the variant lies in the BRCA2 DNA-binding domain, BayesDel no-AF is 0.314702 above the PP3 threshold of 0.30, REVEL is 0.82, and SpliceAI predicts no significant splice effect with a max delta score of 0.02.
No criteria match.
Met · 1
PP3 SupportingThis missense variant lies within the BRCA2 DNA-binding domain (aa 2481-3186). BayesDel no-AF is 0.314702, which is above the ENIGMA PP3 threshold of ≥0.30, REVEL is 0.82, and SpliceAI predicts no significant splice effect (max delta 0.02), supporting a damaging protein effect; therefore PP3 is met at supporting strength. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PP3 for missense variants in a clinically important domain requires BayesDel no-AF ≥0.30.
Evidence considered
- BayesDel no-AF 0.314702.
- REVEL 0.82.
- SpliceAI max delta 0.02.
- Variant position L2654 is within the BRCA2 DNA-binding domain.
Sources
Not met · 10 · evaluated, threshold not reached
PVS1 This variant is a missense substitution, not a nonsense, frameshift, or canonical ±1/2 splice-site variant, and no RNA evidence showing an abnormal loss-of-function transcript was identified. SpliceAI predicts no significant splice impact (max delta 0.02), so PVS1 is not met. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PVS1 is for null variants or qualifying RNA evidence; this missense change does not meet those conditions.
Evidence considered
- BRCA2 is PVS1-eligible at the gene level
- but this specific variant is outside the default PVS1 variant classes.
- SpliceAI max delta score is 0.02.
Still missing
- No variant-specific RNA study was identified.
Sources
PS3 In the ENIGMA BRCA2 functional table, this variant is summarized as having discordant results across two or more calibrated studies. One study reported a damaging effect and another placed the result between benign and pathogenic controls, so the available functional evidence does not support PS3. Details ▾Hide ▴
Rule
ENIGMA Table 9 pre-assigned functional evidence governs PS3/BS3 use.
Evidence considered
- ENIGMA Table 9 entry for c.7961T>C / p.(Leu2654Pro): code None
- strength N/A
- discordant calibrated studies.
Still missing
- Direct review of all underlying assay reports could further refine the interpretation
- but the curated ENIGMA table does not assign PS3.
Sources
PM2 This variant is not absent from population databases. It is present in gnomAD v2.1 at 1/31,406 alleles (AF 3.1841e-05) and in gnomAD v4.1 at 3/1,614,066 alleles (AF 1.85866e-06), so PM2 is not met. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PM2_Supporting requires absence from gnomAD controls.
Evidence considered
- gnomAD v2.1: 1/31
- 406 alleles.
- gnomAD v4.1: 3/1
- 614
- 066 alleles.
Sources
PP4 The BRCA2 clinical-history likelihood ratio for this variant is 1.4293 in 2 probands. This is below the ENIGMA PP4 supporting threshold of ≥2.08, so PP4 is not met. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PP4 requires LR ≥2.08 for supporting strength.
Evidence considered
- Clinical-history LR 1.429301978583683 in 2 probands.
Sources
BA1 Available population data do not reach the BA1 threshold. In gnomAD v4.1, the highest available group maximum filter allele frequency is 4.43e-06, which is below the ENIGMA BA1 threshold of >0.001. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BA1 requires FAF >0.001.
Evidence considered
- gnomAD v4.1 grpmax FAF 4.43e-06.
Sources
BS1 Available population data do not reach the BS1 thresholds. In gnomAD v4.1, the highest available group maximum filter allele frequency is 4.43e-06, which is below the ENIGMA BS1 supporting threshold of >0.00002 and the strong threshold of >0.0001. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BS1 requires FAF >0.00002 for supporting or >0.0001 for strong.
Evidence considered
- gnomAD v4.1 grpmax FAF 4.43e-06.
Sources
BS3 In the ENIGMA BRCA2 functional table, this variant is summarized as having discordant results across calibrated studies rather than a consistent normal-function result. Because the curated table does not assign BS3, the available functional evidence does not support BS3. Details ▾Hide ▴
Rule
ENIGMA Table 9 pre-assigned functional evidence governs PS3/BS3 use.
Evidence considered
- ENIGMA Table 9 entry for c.7961T>C / p.(Leu2654Pro): code None
- strength N/A
- discordant calibrated studies.
Still missing
- Direct review of all underlying assay reports could further refine the interpretation
- but the curated ENIGMA table does not assign BS3.
Sources
BP1 BP1_Strong in the ENIGMA BRCA2 specification applies to missense variants outside clinically important domains with no predicted splice effect. This variant is in the BRCA2 DNA-binding domain, so BP1 is not met. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BP1_Strong requires a missense variant outside the PALB2-binding and DNA-binding domains.
Evidence considered
- Variant position L2654 is within the BRCA2 DNA-binding domain.
- SpliceAI max delta 0.02.
Sources
BP4 Although SpliceAI predicts no significant splice impact (max delta 0.02), this missense variant is in the BRCA2 DNA-binding domain and BayesDel no-AF is 0.314702, which is above the BP4 requirement of ≤0.18. REVEL is also high at 0.82. Therefore BP4 is not met. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BP4 for missense variants in a clinically important domain requires BayesDel no-AF ≤0.18 and SpliceAI ≤0.1.
Evidence considered
- BayesDel no-AF 0.314702.
- REVEL 0.82.
- SpliceAI max delta 0.02.
Sources
BP5 The BRCA2 clinical-history likelihood ratio for this variant is 1.4293 in 2 probands. This is above the ENIGMA BP5 supporting threshold of ≤0.48 and falls in the neutral zone, so BP5 is not met. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BP5 requires LR ≤0.48 for supporting strength.
Evidence considered
- Clinical-history LR 1.429301978583683 in 2 probands.
Sources
Not assessed · 6 · no assessment recorded
PS1 No verified evidence was identified showing that this variant produces the same pathogenic amino-acid change or the same pathogenic splicing effect as a previously classified pathogenic or likely pathogenic BRCA2 variant, so PS1 was not assessed. Details ▾Hide ▴
Rule
Apply only when an appropriate previously classified comparator is confirmed.
Evidence considered
- ENIGMA BRCA2 PS1 requires an established pathogenic/likely pathogenic comparator with the same protein or splicing consequence.
Still missing
- No confirmed PS1 comparator variant was identified from the retrieved materials.
Sources
PS4 No case-control study, odds ratio, or quantitative enrichment data were identified showing this variant is significantly more common in affected individuals than in controls, so PS4 was not assessed. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PS4 requires significant case-control enrichment.
Evidence considered
- ClinVar shows mixed assertions but not case-control enrichment data.
Still missing
- No exact-variant case-control dataset was identified.
- No variant-specific multifactorial posterior table entry was identified in the reviewed materials.
Sources
PM3 No evidence was identified showing this variant in trans with another pathogenic BRCA2 variant in an individual with BRCA2-related Fanconi anemia, so PM3 was not assessed. Details ▾Hide ▴
PP1 No quantitative co-segregation data were identified for this variant, so PP1 was not assessed. Details ▾Hide ▴
BS2 No qualifying observations were identified showing this variant in individuals without features of BRCA2-related Fanconi anemia under the ENIGMA BS2 scoring framework, so BS2 was not assessed. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BS2 requires point-based proband evidence in the absence of Fanconi anemia features.
Evidence considered
- No qualifying BS2 dataset was retrieved.
Still missing
- No BS2 point-based proband evidence was identified.
Sources
BS4 No quantitative non-segregation data were identified for this variant, so BS4 was not assessed. Details ▾Hide ▴
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PS2 VCEPThis criterion is not used in the BRCA2 ENIGMA specification for this framework. Details ▾Hide ▴
PM1 VCEPThis criterion is not used in the BRCA2 ENIGMA specification for this framework, even for missense variants in the DNA-binding domain. Details ▾Hide ▴
PM4 VCEPThis criterion is not used in the BRCA2 ENIGMA specification for this framework. Details ▾Hide ▴
PM5 N/AIn the BRCA2 ENIGMA specification, PM5 is repurposed for protein-truncating variants in exons where a different proven pathogenic truncating variant has been observed. This variant is missense, so PM5 is not applicable. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PM5 applies to qualifying PTC variants, not this missense variant.
Evidence considered
- PM5 candidates artifact states PM5 is repurposed for truncating logic
- not classic same-residue missense PM5.
Sources
PM6 VCEPThis criterion is not used in the BRCA2 ENIGMA specification for this framework. Details ▾Hide ▴
PP2 VCEPThis criterion is not used in the BRCA2 ENIGMA specification for this framework. Details ▾Hide ▴
PP5 VCEPThis criterion is not used in the BRCA2 ENIGMA specification for this framework. Details ▾Hide ▴
BP2 VCEPThis criterion is not used in the BRCA2 ENIGMA specification for this framework. Details ▾Hide ▴
BP3 VCEPThis criterion is not used in the BRCA2 ENIGMA specification for this framework. Details ▾Hide ▴
BP6 VCEPThis criterion is not used in the BRCA2 ENIGMA specification for this framework. Details ▾Hide ▴
BP7 N/ABP7 in this framework is for silent or specified intronic variants, and for RNA-only evidence under defined circumstances. This variant is a missense change in the BRCA2 DNA-binding domain, so BP7 is not applicable. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BP7 is not a standard missense criterion for this variant context.
Evidence considered
- Variant type is missense.
- SpliceAI max delta 0.02.
Sources
Identifiers
- Gene
- BRCA2
- Transcript
- NM_000059.3
- Coding (HGVS c.)
- NM_000059.3:c.7961T>C
- Protein (HGVS p.)
- NP_000050.2:p.(Leu2654Pro)
- GRCh38
- chr13:32362678 T>C
- GRCh37
- chr13:32936815 T>C
- ClinVar
- 52448
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
3 / 1,614,066 alleles
AF 1.86e-06 · 0 homozygotes · FAF 4.43e-06
gnomAD v2.1
1 / 31,406 alleles
AF 3.18e-05 · 0 homozygotes
By genetic ancestry
gnomAD v4.1
AF 1.9e-06 · 3 / 1,614,066 alleles · 0 hom · FAF 4.4e-06
| African/African American2 / 74,936 | 2.7e-05 |
| European (non-Finnish)1 / 1,180,048 | 8.5e-07 |
0 alternate alleles recorded in 8 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish.
gnomAD v2.1
AF 3.2e-05 · 1 / 31,406 alleles · 0 hom
| African/African American1 / 8,712 | 0.00011 |
0 alternate alleles recorded in 7 other groups: Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.85866e-06; MAF= 0.00019%, 3/1614066 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 2.66894e-05; MAF= 0.00267%, 2/74936 alleles, homozygotes = 0); grpmax FAF= 4.43e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.1841e-05; MAF= 0.00318%, 1/31406 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000114784; MAF= 0.01148%, 1/8712 alleles, homozygotes = 0).
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.820
- BayesDel
- 0.315
How the predictions were used
PP3 SupportingThis missense variant lies within the BRCA2 DNA-binding domain (aa 2481-3186). BayesDel no-AF is 0.314702, which is above the ENIGMA PP3 threshold of ≥0.30, REVEL is 0.82, and SpliceAI predicts no significant splice effect (max delta 0.02), supporting a damaging protein effect; therefore PP3 is met at supporting strength. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PP3 for missense variants in a clinically important domain requires BayesDel no-AF ≥0.30.
Evidence considered
- BayesDel no-AF 0.314702.
- REVEL 0.82.
- SpliceAI max delta 0.02.
- Variant position L2654 is within the BRCA2 DNA-binding domain.
Sources
BP4 Although SpliceAI predicts no significant splice impact (max delta 0.02), this missense variant is in the BRCA2 DNA-binding domain and BayesDel no-AF is 0.314702, which is above the BP4 requirement of ≤0.18. REVEL is also high at 0.82. Therefore BP4 is not met. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BP4 for missense variants in a clinically important domain requires BayesDel no-AF ≤0.18 and SpliceAI ≤0.1.
Evidence considered
- BayesDel no-AF 0.314702.
- REVEL 0.82.
- SpliceAI max delta 0.02.
Sources
BP7 N/ABP7 in this framework is for silent or specified intronic variants, and for RNA-only evidence under defined circumstances. This variant is a missense change in the BRCA2 DNA-binding domain, so BP7 is not applicable. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BP7 is not a standard missense criterion for this variant context.
Evidence considered
- Variant type is missense.
- SpliceAI max delta 0.02.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.82. BayesDel score = 0.314702.
7 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 29394989 ↗Assessment of the Clinical Relevance of BRCA2 Missense Variants by Functional and Computational Approaches.Guidugli L et al. · 2018No paper-specific finding is recorded.
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PMID 35736817 ↗Classification of BRCA2 Variants of Uncertain Significance (VUS) Using an ACMG/AMP Model Incorporating a Homology-Directed Repair (HDR) Functional Assay.Hu C et al. · 2022No paper-specific finding is recorded.
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PMID 23108138 ↗A classification model for BRCA2 DNA binding domain missense variants based on homology-directed repair activity.Guidugli L et al. · 2013No paper-specific finding is recorded.
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PMID 23918944 ↗Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers.No paper-specific finding is recorded.
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PMID 25741868 ↗Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.No paper-specific finding is recorded.
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PMID 29884841 ↗Comprehensive annotation of BRCA1 and BRCA2 missense variants by functionally validated sequence-based computational prediction models.Hart SN et al. · 2019No 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
3 / 1,614,066 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.020
Open source ↗
ClinVar
3 Uncertain significance · 1 Uncertain Significance · 1 Likely 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/52448/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/13-32936815-T-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr13-32362678-T-C?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000059.3%3Ac.7961…
- OncoKB ↗www.oncokb.org/gene/BRCA2/L2654P
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=BRCA2+c.7961T%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= 1.85866e-06; MAF= 0.00019%, 3/1614066 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 2.66894e-05; MAF= 0.00267%, 2/74936 alleles, homozygotes = 0); grpmax FAF= 4.43e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.1841e-05; MAF= 0.00318%, 1/31406 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000114784; MAF= 0.01148%, 1/8712 alleles, homozygotes = 0).
ClinVar
This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories) and as Uncertain Significance (1 clinical laboratory) and as Likely pathogenic (1 clinical laboratory) and as Uncertain Significance by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 52448)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.82. BayesDel score = 0.314702.
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.