About BRCA2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRCA2 c.9227G>T, p.(Gly3076Val)
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 calibrated functional dataset, c.9227G>T (p.Gly3076Val) showed abnormal function similar to pathogenic control variants, supporting PS3 at strong strength.
PP3Supporting
PP3 · supporting
This missense variant lies within the BRCA2 DNA-binding domain (amino acids 2481-3186). BayesDel no-AF is 0.377938, which is above the ENIGMA PP3 threshold of 0.30, REVEL is 0.884, and SpliceAI predicts no significant splice effect (max delta 0.07), supporting a damaging protein effect consistent with PP3.
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: Likely pathogenic
ENIGMA BRCA1/2 VCEP v1.2 Table 3 combining rules applied from the official final-classification framework: 1 Strong pathogenic criterion plus 2 Supporting pathogenic criteria.
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
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
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 · 9 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.9227G>T (p.Gly3076Val) variant has not been observed in COSMIC and has been reported in ClinVar, including a Pathogenic expert-panel classification from ClinGen ENIGMA.
This variant is absent from gnomAD v2.1 and gnomAD v4.1, which supports rarity, although the site-level depth information required for formal ENIGMA PM2_Supporting application was not identified here.
In the ENIGMA BRCA2 calibrated functional dataset, p.(Gly3076Val) showed abnormal function similar to pathogenic control variants, supporting PS3 at strong strength.
This missense change lies within the BRCA2 DNA-binding domain; BayesDel no-AF is 0.377938, REVEL is 0.884, and SpliceAI max delta is 0.07, supporting a damaging protein effect without a predicted splice effect and therefore supporting PP3 but not BP4.
No criteria match.
Met · 3
PS3 StrongIn the ENIGMA BRCA2 calibrated functional dataset, c.9227G>T (p.Gly3076Val) showed abnormal function similar to pathogenic control variants, supporting PS3 at strong strength. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PS3 is applied using calibrated published functional assays summarized in Table 9.
Evidence considered
- Table 9 row for BRCA2 c.9227G>T p.(Gly3076Val): PS3 Strong.
- Functional summary states the variant was damaging in one calibrated study.
Sources
PP3 SupportingThis missense variant lies within the BRCA2 DNA-binding domain (amino acids 2481-3186). BayesDel no-AF is 0.377938, which is above the ENIGMA PP3 threshold of 0.30, REVEL is 0.884, and SpliceAI predicts no significant splice effect (max delta 0.07), supporting a damaging protein effect consistent with PP3. Details ▾Hide ▴
Rule
For BRCA2 missense variants inside a clinically important functional domain, PP3 applies when BayesDel no-AF is ≥0.30.
Evidence considered
- Protein change p.(Gly3076Val) is within the BRCA2 DNA-binding domain.
- BayesDel no-AF score = 0.377938.
- REVEL score = 0.884.
- SpliceAI max delta score = 0.07.
Sources
PP5 SupportingExpert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Pathogenic. Details ▾Hide ▴
Not met · 9 · evaluated, threshold not reached
PVS1 This variant is a missense substitution, not a nonsense, frameshift, initiation-loss, or canonical ±1,2 splice variant. SpliceAI predicts no significant splice effect (max delta 0.07), so available evidence does not support a BRCA2 loss-of-function mechanism for PVS1. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PVS1 applies to null variants or qualifying RNA evidence; neither was identified for this missense change.
Evidence considered
- BRCA2 is eligible for PVS1 in principle under ENIGMA rules.
- Variant-level PVS1 scaffold classifies this change outside generic null-variant buckets.
- SpliceAI max delta score is 0.07.
Still missing
- No exact-variant RNA study was identified to show an abnormal transcript effect that would justify PVS1(RNA).
Sources
PP4 The BRCA2 clinical-history likelihood ratio for c.9227G>T is 0.776 with 1 proband, which is below the ENIGMA PP4 supporting threshold of 2.08. This value does not support PP4. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PP4 uses calibrated clinical-history likelihood ratios toward pathogenicity.
Evidence considered
- Clinical-history LR = 0.7760849145466545.
- N_Probands = 1.
- PP4 Supporting threshold = LR ≥2.08.
Sources
BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore is not above the ENIGMA BA1 threshold of filter allele frequency greater than 0.1%. Details ▾Hide ▴
Rule
BA1 requires a high population frequency above the BRCA2 ENIGMA stand-alone benign threshold.
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
- BA1 threshold: FAF >0.001.
Sources
BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore is not above the ENIGMA BS1 thresholds of filter allele frequency greater than 0.002% or 0.01%. Details ▾Hide ▴
Rule
BS1 requires population frequency above the BRCA2 ENIGMA benign threshold.
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
- BS1 Supporting threshold: FAF >0.00002.
- BS1 Strong threshold: FAF >0.0001.
Sources
BS3 Available calibrated functional evidence showed an abnormal damaging effect rather than normal function, so BS3 is not supported for this variant. Details ▾Hide ▴
Rule
BS3 requires well-established functional studies showing no damaging effect on protein function.
Evidence considered
- Table 9 assigns PS3 Strong
- not BS3
- for c.9227G>T p.(Gly3076Val).
Sources
BP1 This missense variant lies within the BRCA2 DNA-binding domain (amino acids 2481-3186), so it does not meet the ENIGMA BP1 rule, which is limited to missense or silent changes outside clinically important functional domains with no predicted splice effect. Details ▾Hide ▴
Rule
BP1_Strong applies only outside the BRCA2 PALB2-binding and DNA-binding domains when splicing is not predicted to be affected.
Evidence considered
- Protein position 3076 is within the BRCA2 DNA-binding domain.
- SpliceAI max delta score = 0.07.
Sources
BP4 Although SpliceAI predicts no significant splice effect (max delta 0.07, below the BP4 threshold of 0.1), BayesDel no-AF is 0.377938, which is above the benign BP4 threshold of 0.18. Available computational evidence therefore does not support BP4. Details ▾Hide ▴
Rule
For BRCA2 missense variants inside a clinically important functional domain, BP4 requires BayesDel no-AF ≤0.18 and SpliceAI ≤0.1.
Evidence considered
- BayesDel no-AF score = 0.377938.
- SpliceAI max delta score = 0.07.
- BP4 inside-domain threshold requires BayesDel ≤0.18 and SpliceAI ≤0.1.
Sources
BP5 The BRCA2 clinical-history likelihood ratio for c.9227G>T is 0.776 with 1 proband, which is above the ENIGMA BP5 supporting threshold of 0.48. This value does not support BP5. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BP5 uses calibrated clinical-history likelihood ratios against pathogenicity.
Evidence considered
- Clinical-history LR = 0.7760849145466545.
- N_Probands = 1.
- BP5 Supporting threshold = LR ≤0.48.
Sources
BP7 This is a missense variant within a clinically important BRCA2 functional domain, and no RNA evidence showing a benign transcript effect was identified. Available evidence therefore does not support BP7. Details ▾Hide ▴
Rule
BP7 in this framework depends on benign RNA evidence or specific silent/intronic contexts not met here.
Evidence considered
- Variant is a missense change in the BRCA2 DNA-binding domain.
- SpliceAI max delta score = 0.07.
- No benign RNA assay evidence was identified.
Still missing
- No exact-variant mRNA assay showing a benign transcript effect was identified.
Sources
Not assessed · 7 · no assessment recorded
PS1 No previously classified variant with the same proven amino-acid change or the same demonstrated splice effect was identified here, so PS1 could not be assessed from the available evidence. Details ▾Hide ▴
Rule
Apply PS1 only when the same amino-acid substitution or same splice consequence has already been established for an appropriate reference variant.
Evidence considered
- ENIGMA BRCA2 PS1 requires the same protein change or the same splice effect as a previously classified pathogenic or likely pathogenic variant.
Still missing
- A same-amino-acid pathogenic reference variant was not identified.
- A same-splice-effect pathogenic reference variant was not identified.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
PS4 This variant has been reported in ClinVar, but no case-control study, odds ratio, or other quantitative prevalence evidence meeting the ENIGMA PS4 rule was identified here. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PS4 requires a significant increase in affected individuals versus controls based on case-control evidence.
Evidence considered
- ClinVar contains submissions for this variant.
- No exact-variant hit was identified in the reviewed ENIGMA supplementary posterior table or Parsons multifactorial workbook.
Still missing
- No verified case-control estimate with p-value and odds ratio meeting ENIGMA PS4 thresholds was identified.
- No exact-variant posterior-probability or multifactorial prevalence entry was identified in the reviewed BRCA2 summary tables.
Sources
clinvar ↗vcep_supplementarytables_v1_2_2024_11_18vcep_humu_40_1557_s001vcep_specifications_v1_2_2024_11_18
PM2 This variant is absent from gnomAD v2.1 and gnomAD v4.1, which supports rarity. However, the ENIGMA PM2_Supporting rule also requires adequate local read depth, and site-level depth information was not identified here. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PM2 is Supporting only when absent from controls and the region has adequate average read depth.
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
Still missing
- Average read depth ≥25 at this site was not identified from the reviewed materials.
- The ENIGMA rule references gnomAD v3.1 specifically
- only v2.1 and v4.1 absence was available here.
Sources
PM3 No evidence was identified that this variant was observed in trans with another BRCA2 variant in an individual with a phenotype consistent with BRCA2-related Fanconi anemia, so PM3 could not be assessed. Details ▾Hide ▴
Rule
Apply PM3 only in qualifying BRCA2-related Fanconi anemia cases with defined point-based evidence.
Evidence considered
- ENIGMA BRCA2 PM3 is restricted to recessive Fanconi anemia contexts.
Still missing
- No phase data were identified.
- No BRCA2-related Fanconi anemia phenotype data were identified.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
PP1 No segregation data were identified for this variant, so PP1 could not be assessed. Details ▾Hide ▴
Rule
Apply PP1 only with quantified segregation likelihood ratios meeting ENIGMA thresholds.
Evidence considered
- ENIGMA BRCA2 PP1 requires quantitative cosegregation evidence.
Still missing
- No family-based likelihood ratio or quantitative cosegregation analysis was identified.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
BS2 No qualifying observations in individuals without features of BRCA2-related Fanconi anemia were identified for the ENIGMA BS2 point-based rule, so BS2 could not be assessed. Details ▾Hide ▴
Rule
Apply BS2 only with qualifying point-based evidence under the BRCA2 ENIGMA specification.
Evidence considered
- ENIGMA BRCA2 BS2 uses a Fanconi-anemia-specific point system.
Still missing
- No BS2 point assignments or qualifying proband data were identified.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
BS4 No non-segregation data with a quantitative likelihood ratio were identified for this variant, so BS4 could not be assessed. Details ▾Hide ▴
Rule
Apply BS4 only with quantified lack-of-segregation evidence meeting ENIGMA thresholds.
Evidence considered
- ENIGMA BRCA2 BS4 requires quantitative non-segregation evidence.
- No exact-variant segregation entry was identified in the reviewed summary tables.
Still missing
- No family-based non-segregation likelihood ratio meeting ENIGMA thresholds was identified.
Sources
cspec ↗vcep_supplementarytables_v1_2_2024_11_18vcep_humu_40_1557_s001vcep_specifications_v1_2_2024_11_18
Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴
PS2 N/ADe novo occurrence is not an applicable criterion in this BRCA2 ENIGMA framework for this review. Details ▾Hide ▴
Rule
Not applicable in the BRCA2 ENIGMA specification.
Evidence considered
- CSPEC lists PS2 as not applicable.
Sources
PM1 N/APM1 is not an applicable criterion in this BRCA2 ENIGMA framework for this review. Details ▾Hide ▴
Rule
Not applicable in the BRCA2 ENIGMA specification.
Evidence considered
- CSPEC lists PM1 as not applicable.
Sources
PM4 N/APM4 is not an applicable criterion in this BRCA2 ENIGMA framework for this review. Details ▾Hide ▴
Rule
Not applicable in the BRCA2 ENIGMA specification.
Evidence considered
- CSPEC lists PM4 as not applicable.
Sources
PM5 N/AIn this BRCA2 ENIGMA framework, PM5 is defined for protein-truncating variants already annotated with PVS1. This variant is a missense substitution, so that PM5 rule does not apply. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PM5 here is the PTC-specific rule, not the generic same-residue missense rule.
Evidence considered
- CSPEC PM5 rule is limited to protein termination codon variants in eligible exons.
- This variant is p.(Gly3076Val)
- a missense change.
Sources
PM6 N/APM6 is not an applicable criterion in this BRCA2 ENIGMA framework for this review. Details ▾Hide ▴
Rule
Not applicable in the BRCA2 ENIGMA specification.
Evidence considered
- CSPEC lists PM6 as not applicable.
Sources
PP2 N/APP2 is not an applicable criterion in this BRCA2 ENIGMA framework for this review. Details ▾Hide ▴
Rule
Not applicable in the BRCA2 ENIGMA specification.
Evidence considered
- CSPEC lists PP2 as not applicable.
Sources
BP2 N/ABP2 is not an applicable criterion in this BRCA2 ENIGMA framework for this review. Details ▾Hide ▴
Rule
Not applicable in the BRCA2 ENIGMA specification.
Evidence considered
- CSPEC lists BP2 as not applicable.
Sources
BP3 N/ABP3 is not an applicable criterion in this BRCA2 ENIGMA framework for this review. Details ▾Hide ▴
Rule
Not applicable in the BRCA2 ENIGMA specification.
Evidence considered
- CSPEC lists BP3 as not applicable.
Sources
BP6 N/ABP6 is not an applicable criterion in this BRCA2 ENIGMA framework for this review. Details ▾Hide ▴
Rule
Not applicable in the BRCA2 ENIGMA specification.
Evidence considered
- CSPEC lists BP6 as not applicable.
Sources
Identifiers
- Gene
- BRCA2
- Transcript
- NM_000059.3
- Coding (HGVS c.)
- NM_000059.3:c.9227G>T
- Protein (HGVS p.)
- NP_000050.2:p.(Gly3076Val)
- GRCh38
- chr13:32380116 G>T
- GRCh37
- chr13:32954253 G>T
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
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
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 (amino acids 2481-3186). BayesDel no-AF is 0.377938, which is above the ENIGMA PP3 threshold of 0.30, REVEL is 0.884, and SpliceAI predicts no significant splice effect (max delta 0.07), supporting a damaging protein effect consistent with PP3. Details ▾Hide ▴
Rule
For BRCA2 missense variants inside a clinically important functional domain, PP3 applies when BayesDel no-AF is ≥0.30.
Evidence considered
- Protein change p.(Gly3076Val) is within the BRCA2 DNA-binding domain.
- BayesDel no-AF score = 0.377938.
- REVEL score = 0.884.
- SpliceAI max delta score = 0.07.
Sources
BP4 Although SpliceAI predicts no significant splice effect (max delta 0.07, below the BP4 threshold of 0.1), BayesDel no-AF is 0.377938, which is above the benign BP4 threshold of 0.18. Available computational evidence therefore does not support BP4. Details ▾Hide ▴
Rule
For BRCA2 missense variants inside a clinically important functional domain, BP4 requires BayesDel no-AF ≤0.18 and SpliceAI ≤0.1.
Evidence considered
- BayesDel no-AF score = 0.377938.
- SpliceAI max delta score = 0.07.
- BP4 inside-domain threshold requires BayesDel ≤0.18 and SpliceAI ≤0.1.
Sources
BP7 This is a missense variant within a clinically important BRCA2 functional domain, and no RNA evidence showing a benign transcript effect was identified. Available evidence therefore does not support BP7. Details ▾Hide ▴
Rule
BP7 in this framework depends on benign RNA evidence or specific silent/intronic contexts not met here.
Evidence considered
- Variant is a missense change in the BRCA2 DNA-binding domain.
- SpliceAI max delta score = 0.07.
- No benign RNA assay evidence was identified.
Still missing
- No exact-variant mRNA assay showing a benign transcript effect was identified.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07). REVEL score = 0.884. BayesDel score = 0.377938.
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
Captured gnomAD v4.1 source record
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/126203/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/13-32954253-G-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr13-32380116-G-T?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000059.3%3Ac.9227…
- OncoKB ↗www.oncokb.org/gene/BRCA2/G3076V
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=BRCA2+c.9227G%3ET
- 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
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant has been reported in ClinVar as Pathogenic (3 clinical laboratories) and as Uncertain significance (2 clinical laboratories) and as Likely pathogenic (1 clinical laboratory) and as 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 = 0.07). REVEL score = 0.884. BayesDel score = 0.377938.
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.