About BRCA2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRCA2 c.9117G>A, p.(Pro3039=)
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 synonymous variant affects the last nucleotide of exon 23. In a published RNA study using puromycin-treated lymphocytes, this variant caused exon 23 skipping. Exon 23 is 164 nucleotides long, so complete skipping is out of frame, and ENIGMA Table 4 assigns exon 23 loss/spliceogenic RNA events to PVS1/PVS1(RNA). Because BRCA2 loss of function is an established disease mechanism, this supports PVS1 at very strong strength.
PP3Supporting
PP3 · supporting
Computational splicing evidence supports a deleterious splice effect. SpliceAI predicts strong splice disruption with a maximum delta score of 0.89, which is above the ENIGMA PP3 threshold of 0.2 for predicted splicing impact in silent variants.
PP4Supporting
PP4 · supporting
Clinical-history likelihood analysis supports pathogenicity. In the BRCA2-specific Li et al. dataset, this variant had an LR of 3.91 in 12 probands, which is above the ENIGMA PP4 Supporting threshold of 2.08 and below the Moderate threshold of 4.3.
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 final-classification framework (Table 3 criteria-combination rules via CSPEC/VCEP override).
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
6 / 1,613,038 alleles
gnomAD v4.1: 6 / 1,613,038 alleles. Recorded AF 3.71969e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 4.02612e-06; MAF= 0.00040%, 1/248378 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.95576e-06; MAF= 0.00090%, 1/111660 alleles, homozygotes = 0).
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 curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
No listed criterion applied
OncoKB ↗
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 · 8 not met · 7 not assessed · 9 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.9117G>A (p.Pro3039=) variant has been reported in ClinVar as Pathogenic with expert panel review.
This variant is rare in population databases, with AF 4.03e-06 (1/248378 alleles) in gnomAD v2.1 and AF 3.72e-06 (6/1613038 alleles) in gnomAD v4.1.
In a published RNA study, this variant caused exon 23 skipping in puromycin-treated lymphocytes, supporting an abnormal splicing effect consistent with loss of function.
SpliceAI predicts strong splice disruption with a maximum delta score of 0.89, which supports a deleterious splicing effect.
In the BRCA2-specific clinical-history likelihood dataset, this variant had an LR of 3.91 in 12 probands, meeting ENIGMA PP4 at supporting strength.
No criteria match.
Met · 4
PVS1 Very strongThis synonymous variant affects the last nucleotide of exon 23. In a published RNA study using puromycin-treated lymphocytes, this variant caused exon 23 skipping. Exon 23 is 164 nucleotides long, so complete skipping is out of frame, and ENIGMA Table 4 assigns exon 23 loss/spliceogenic RNA events to PVS1/PVS1(RNA). Because BRCA2 loss of function is an established disease mechanism, this supports PVS1 at very strong strength. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PVS1 / PVS1(RNA)
Evidence considered
- BRCA2 loss of function established in gene-specific framework
- RNA study reported exon 23 skipping for c.9117G>A
- Exon 23 annotated as PVS1/PVS1(RNA)-eligible in ENIGMA Table 4
Sources
cspec ↗pvs1_gene_contextpvs1_variant_assessmentvcep_pmid_22505045_houdayer_2012_hummutatvcep_specifications_table4_v1_2_2024_11_18vcep_specifications_v1_2_2024_11_18
PP3 SupportingComputational splicing evidence supports a deleterious splice effect. SpliceAI predicts strong splice disruption with a maximum delta score of 0.89, which is above the ENIGMA PP3 threshold of 0.2 for predicted splicing impact in silent variants. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PP3 predicted splicing rule
Evidence considered
- SpliceAI max delta 0.89
Sources
PP4 SupportingClinical-history likelihood analysis supports pathogenicity. In the BRCA2-specific Li et al. dataset, this variant had an LR of 3.91 in 12 probands, which is above the ENIGMA PP4 Supporting threshold of 2.08 and below the Moderate threshold of 4.3. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PP4 clinical-history LR rule
Evidence considered
- Clinical-history LR 3.910369863346765
- N probands 12
Sources
Not met · 8 · evaluated, threshold not reached
PM2 This variant is not absent from controls. It is present in gnomAD v2.1 at 1/248378 alleles (AF 4.03e-06) and in gnomAD v4.1 at 6/1613038 alleles (AF 3.72e-06), so the ENIGMA PM2 absence requirement is not met. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PM2 requires absence from controls
Evidence considered
- gnomAD v2.1 observed AC 1
- gnomAD v4.1 observed AC 6
Sources
BA1 Population frequency does not meet the ENIGMA BA1 threshold. The highest reviewed frequency is 3.72e-06 in gnomAD v4.1, which is far below the BA1 cutoff of 0.001. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BA1 frequency rule
Evidence considered
- gnomAD v4.1 AF 3.71969e-06
- BA1 threshold 0.001
Sources
BS1 Population frequency does not meet the ENIGMA BS1 threshold. The highest reviewed frequency is 3.72e-06 in gnomAD v4.1, which is below the BS1 Supporting threshold of 0.00002 and far below the Strong threshold of 0.0001. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BS1 frequency rule
Evidence considered
- gnomAD v4.1 AF 3.71969e-06
- BS1 Supporting threshold 0.00002
- BS1 Strong threshold 0.0001
Sources
BS3 Available functional evidence does not support a benign effect. Instead, RNA studies showed exon 23 skipping, which is consistent with an abnormal splicing effect rather than no damaging effect. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BS3 rule
Evidence considered
- Published RNA study showed exon 23 skipping
- no exact-variant BS3 entry located in Table 9
Still missing
- No qualifying benign functional assay was identified for this exact variant.
Sources
vcep_pmid_22505045_houdayer_2012_hummutatvcep_specifications_table9_v1_2_2024_11_18vcep_specifications_v1_2_2024_11_18
BP1 This silent variant does not meet ENIGMA BP1_Strong because predicted splice impact is present. SpliceAI is 0.89, which is above the no-splicing-impact threshold of 0.1. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BP1_Strong rule
Evidence considered
- SpliceAI max delta 0.89
Sources
BP4 This silent variant does not meet BP4 because ENIGMA requires no predicted splice impact for a silent variant in a clinically important functional domain, with SpliceAI at or below 0.1. The observed SpliceAI maximum delta score is 0.89, which is above that threshold. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BP4 rule
Evidence considered
- SpliceAI max delta 0.89
- BP4 threshold <=0.1
Sources
BP5 Clinical-history likelihood analysis does not support a benign interpretation. The variant-level LR is 3.91 in 12 probands, which is above the benign BP5 threshold of 0.48 rather than at or below it. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BP5 clinical-history LR rule
Evidence considered
- Clinical-history LR 3.910369863346765
- BP5 threshold <=0.48
Sources
BP7 This silent variant does not meet BP7. ENIGMA requires either BP4 for silent variants in a clinically important functional domain or RNA evidence showing no damaging transcript effect. Here, SpliceAI is 0.89 and published RNA studies showed exon 23 skipping, so the evidence argues against BP7. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BP7 rule
Evidence considered
- SpliceAI max delta 0.89
- Published RNA study showed exon 23 skipping
Sources
Not assessed · 7 · no assessment recorded
PS1 Available evidence confirms abnormal splicing for this variant, but the reviewed materials do not establish a same-effect reference pathogenic variant under the ENIGMA PS1 splicing framework strongly enough to assign PS1 here. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PS1 splicing rule
Evidence considered
- PS1 in BRCA2 can be applied for same predicted splicing impact as a classified pathogenic variant
Still missing
- No directly reviewed Table 5 or equivalent same-effect comparison was identified for PS1 assignment.
Sources
PS3 RNA studies showed exon 23 skipping, but ENIGMA directs mRNA-only damaging evidence to PVS1(RNA) rather than PS3. No qualifying protein-based or combined protein-plus-RNA functional study was identified for separate PS3 assignment. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PS3 / PVS1(RNA) separation
Evidence considered
- mRNA-only damaging evidence captured under PVS1(RNA)
- no exact-variant PS3 entry located in Table 9
Still missing
- No qualifying protein-focused functional assay was identified for this exact variant.
Sources
cspec ↗vcep_pmid_22505045_houdayer_2012_hummutatvcep_specifications_v1_2_2024_11_18vcep_specifications_table9_v1_2_2024_11_18
PS4 This variant has been reported in affected individuals and appears in the ENIGMA reference-set materials with a very high posterior probability, but the reviewed materials do not provide a qualifying case-control odds ratio and p-value meeting the ENIGMA PS4 rule. PS4 was therefore not independently assigned here. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PS4 requires case-control enrichment
Evidence considered
- ClinVar expert panel pathogenic classification
- ENIGMA ST7 posterior probability 0.99978770505
- IARC class 5
Still missing
- No qualifying case-control comparison with OR and p-value meeting ENIGMA PS4 thresholds was directly reviewed.
Sources
PM3 No evidence was identified that this variant was observed in trans with another BRCA2 variant in a proband with BRCA2-related Fanconi anemia, so PM3 was not assessed. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PM3 rule
Evidence considered
- PM3 in BRCA2 is restricted to Fanconi anemia context
Still missing
- No recessive Fanconi anemia case-level data were identified.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
PP1 No quantitative co-segregation likelihood ratio for this exact variant was identified in the reviewed materials, so PP1 was not assessed. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PP1 rule
Evidence considered
- PP1 requires quantitative segregation LR
Still missing
- No variant-specific segregation LR meeting ENIGMA PP1 thresholds was directly reviewed.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
BS2 No informative evidence was identified showing this variant in individuals without features of BRCA2-related Fanconi anemia at a level that would satisfy the ENIGMA BS2 point-based framework. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BS2 rule
Evidence considered
- BS2 in BRCA2 is evaluated in Fanconi anemia context
Still missing
- No BS2 point-based case data were identified.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
BS4 No quantitative lack-of-segregation likelihood ratio for this exact variant was identified in the reviewed materials, so BS4 was not assessed. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BS4 rule
Evidence considered
- BS4 requires quantitative non-segregation LR
Still missing
- No variant-specific non-segregation LR meeting ENIGMA BS4 thresholds was directly reviewed.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴
PS2 N/AENIGMA BRCA2 v1.2 marks PS2 as not applicable in this framework. Details ▾Hide ▴
Rule
Not applicable in ENIGMA BRCA2 v1.2
Evidence considered
- CSPEC applicability statement
Sources
PM1 N/AENIGMA BRCA2 v1.2 marks PM1 as not applicable in this framework. Details ▾Hide ▴
Rule
Not applicable in ENIGMA BRCA2 v1.2
Evidence considered
- CSPEC applicability statement
Sources
PM4 N/AENIGMA BRCA2 v1.2 marks PM4 as not applicable in this framework. Details ▾Hide ▴
Rule
Not applicable in ENIGMA BRCA2 v1.2
Evidence considered
- CSPEC applicability statement
Sources
PM5 N/APM5 in this framework applies to missense substitutions at the same residue or to eligible protein-termination codon events. This variant is synonymous and is not a protein-termination codon variant, so PM5 is not applicable. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PM5 rule
Evidence considered
- PM5 framework limited to missense/PTC contexts
Sources
PM6 N/AENIGMA BRCA2 v1.2 marks PM6 as not applicable in this framework. Details ▾Hide ▴
Rule
Not applicable in ENIGMA BRCA2 v1.2
Evidence considered
- CSPEC applicability statement
Sources
PP2 N/AENIGMA BRCA2 v1.2 marks PP2 as not applicable in this framework. Details ▾Hide ▴
Rule
Not applicable in ENIGMA BRCA2 v1.2
Evidence considered
- CSPEC applicability statement
Sources
BP2 N/AENIGMA BRCA2 v1.2 marks BP2 as not applicable in this framework. Details ▾Hide ▴
Rule
Not applicable in ENIGMA BRCA2 v1.2
Evidence considered
- CSPEC applicability statement
Sources
BP3 N/AENIGMA BRCA2 v1.2 marks BP3 as not applicable in this framework. Details ▾Hide ▴
Rule
Not applicable in ENIGMA BRCA2 v1.2
Evidence considered
- CSPEC applicability statement
Sources
BP6 N/AENIGMA BRCA2 v1.2 marks BP6 as not applicable in this framework. Details ▾Hide ▴
Rule
Not applicable in ENIGMA BRCA2 v1.2
Evidence considered
- CSPEC applicability statement
Sources
Identifiers
- Gene
- BRCA2
- Transcript
- NM_000059.3
- Coding (HGVS c.)
- NM_000059.3:c.9117G>A
- Protein (HGVS p.)
- NP_000050.2:p.(Pro3039=)
- GRCh38
- chr13:32379913 G>A
- GRCh37
- chr13:32954050 G>A
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
6 / 1,613,038 alleles
AF 3.72e-06 · 0 homozygotes · FAF 1.83e-06
gnomAD v2.1
1 / 248,378 alleles
AF 4.03e-06 · 0 homozygotes
By genetic ancestry
gnomAD v4.1
AF 3.7e-06 · 6 / 1,613,038 alleles · 0 hom · FAF 1.8e-06
| European (non-Finnish)6 / 1,179,458 | 5.1e-06 |
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.
gnomAD v2.1
AF 4e-06 · 1 / 248,378 alleles · 0 hom
| European (non-Finnish)1 / 111,660 | 9e-06 |
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 3.71969e-06; MAF= 0.00037%, 6/1613038 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 5.08708e-06; MAF= 0.00051%, 6/1179458 alleles, homozygotes = 0); grpmax FAF= 1.83e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 4.02612e-06; MAF= 0.00040%, 1/248378 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.95576e-06; MAF= 0.00090%, 1/111660 alleles, homozygotes = 0).
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 SupportingComputational splicing evidence supports a deleterious splice effect. SpliceAI predicts strong splice disruption with a maximum delta score of 0.89, which is above the ENIGMA PP3 threshold of 0.2 for predicted splicing impact in silent variants. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PP3 predicted splicing rule
Evidence considered
- SpliceAI max delta 0.89
Sources
BP4 This silent variant does not meet BP4 because ENIGMA requires no predicted splice impact for a silent variant in a clinically important functional domain, with SpliceAI at or below 0.1. The observed SpliceAI maximum delta score is 0.89, which is above that threshold. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BP4 rule
Evidence considered
- SpliceAI max delta 0.89
- BP4 threshold <=0.1
Sources
BP7 This silent variant does not meet BP7. ENIGMA requires either BP4 for silent variants in a clinically important functional domain or RNA evidence showing no damaging transcript effect. Here, SpliceAI is 0.89 and published RNA studies showed exon 23 skipping, so the evidence argues against BP7. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BP7 rule
Evidence considered
- SpliceAI max delta 0.89
- Published RNA study showed exon 23 skipping
Sources
Statement
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.89).
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
6 / 1,613,038 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/38215/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/13-32954050-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr13-32379913-G-A?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000059.3%3Ac.9117…
- OncoKB ↗www.oncokb.org/gene/BRCA2/P3039=
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=123601560
- 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= 3.71969e-06; MAF= 0.00037%, 6/1613038 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 5.08708e-06; MAF= 0.00051%, 6/1179458 alleles, homozygotes = 0); grpmax FAF= 1.83e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 4.02612e-06; MAF= 0.00040%, 1/248378 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.95576e-06; MAF= 0.00090%, 1/111660 alleles, homozygotes = 0).
ClinVar
This variant has been reported in ClinVar as Pathogenic (32 clinical laboratories) and as pathogenic (1 clinical laboratory) and as Pathogenic by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel).
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.89).
Functional
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV99061599, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.