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
This variant has a calibrated BRCA2 functional assay result showing a damaging effect on protein function. ENIGMA Table 9 assigns PS3 Strong for c.9227G>T (p.Gly3076Val).
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, which supports rarity in population databases and is consistent with PM2_Supporting.
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 and BRCA2 Specification v1.2.0 final-classification framework (Table 3 criteria-combination rules via 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
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
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 Likely Oncogenic; biological effect: Likely Loss-of-function.
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.9227G>T (p.Gly3076Val) variant has not been observed in COSMIC and has been reported in ClinVar, where the overall classification is Pathogenic with expert panel review by the ClinGen ENIGMA BRCA1/BRCA2 Variant Curation Expert Panel.
This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population reference datasets.
A calibrated BRCA2 functional assay summarized in ENIGMA Table 9 supports a damaging effect on protein function, and this evidence meets PS3 at Strong strength.
SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.07, which is below the ENIGMA PP3 splice threshold of 0.20 and below the BP4 splice threshold of 0.10.
No criteria match.
Met · 3
PS3 StrongThis variant has a calibrated BRCA2 functional assay result showing a damaging effect on protein function. ENIGMA Table 9 assigns PS3 Strong for c.9227G>T (p.Gly3076Val). Details ▾Hide ▴
Rule
ENIGMA BRCA2 PS3 applies to well-established functional studies showing a damaging effect.
Evidence considered
- Specifications Table 9 lists BRCA2 c.9227G>T p.(Gly3076Val) as PS3 Strong.
- The table notes one calibrated study reporting protein function similar to pathogenic control variants.
Sources
PM2 SupportingThis variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, which supports rarity in population databases and is consistent with PM2_Supporting. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PM2 applies at Supporting strength for absence from controls in gnomAD.
Evidence considered
- gnomAD v2.1: absent.
- gnomAD v4.1: absent.
Still missing
- The reviewed evidence did not provide the explicit ENIGMA-referenced gnomAD v3.1/read-depth details.
Sources
PP5 SupportingExpert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Pathogenic. Details ▾Hide ▴
Not met · 8 · evaluated, threshold not reached
PVS1 This variant is a missense change, NM_000059.4:c.9227G>T (p.Gly3076Val, p.G3076V), and does not fall into the BRCA2 null-variant categories used for PVS1. No RNA-only evidence was identified to show a transcript effect that would justify PVS1(RNA). Details ▾Hide ▴
Rule
ENIGMA BRCA2 PVS1 applies to qualifying null variants or qualifying RNA evidence.
Evidence considered
- BRCA2 loss of function is an established disease mechanism in the ENIGMA framework.
- The variant-specific PVS1 assessment states that this variant is not a nonsense
- frameshift
- or canonical ±1
- 2 splice variant.
Sources
PP4 The BRCA2 clinical-history likelihood ratio for this variant is 0.776 in 1 proband, which is below the PP4 supporting threshold of 2.08. This value does not support pathogenic clinical-history evidence. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PP4 uses multifactorial clinical-history LR thresholds.
Evidence considered
- Clinical-history LR = 0.7760849145466545.
- N_Probands = 1.
- PP4 requires LR ≥2.08 for Supporting strength.
Sources
BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore is far below the BA1 stand-alone benign threshold of FAF greater than 0.001. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BA1 requires high population frequency.
Evidence considered
- gnomAD v2.1: absent.
- gnomAD v4.1: absent.
- BA1 requires FAF >0.001.
Sources
BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore is below both the BS1 supporting threshold of FAF greater than 0.00002 and the BS1 strong threshold of FAF greater than 0.0001. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BS1 requires population frequency above defined FAF thresholds.
Evidence considered
- gnomAD v2.1: absent.
- gnomAD v4.1: absent.
- BS1 Supporting requires FAF >0.00002
- BS1 Strong requires FAF >0.0001.
Sources
BS3 Available calibrated functional evidence shows a damaging effect on BRCA2 protein function rather than normal function, so BS3 is not met. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BS3 requires well-established studies showing no damaging effect.
Evidence considered
- ENIGMA Table 9 assigns PS3 Strong
- not BS3
- for BRCA2 c.9227G>T p.(Gly3076Val).
Sources
BP1 This missense variant affects residue 3076 within the BRCA2 DNA-binding region (amino acids 2481-3186), so it is not outside a clinically important functional domain. Available functional evidence also supports a damaging effect, which argues against BP1_Strong. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BP1_Strong applies to missense or silent variants outside clinically important domains with no predicted splicing impact.
Evidence considered
- ENIGMA defines the BRCA2 DNA-binding domain as amino acids 2481-3186.
- p.Gly3076Val lies within that domain.
- Functional evidence supports a damaging effect.
Sources
cspec ↗vcep_specifications_table9_v1_2_2024_11_18
BP4 SpliceAI predicts no significant splice impact for this variant (max delta score 0.07, below the BP4 splice threshold of 0.10), but ENIGMA BP4 for a missense variant inside a clinically important domain also requires BayesDel no-AF less than or equal to 0.18 and no predicted impact via protein change. Those benign missense conditions were not met from the available evidence, and calibrated functional data support a damaging effect. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BP4 requires benign computational evidence under the specification thresholds.
Evidence considered
- SpliceAI max delta score = 0.07.
- The variant lies in the BRCA2 DNA-binding domain.
- ENIGMA Table 9 supports a damaging functional effect.
Still missing
- No BayesDel no-AF score supporting BP4 was identified.
Sources
BP5 The BRCA2 clinical-history likelihood ratio for this variant is 0.776 in 1 proband, which is above the BP5 supporting threshold of 0.48. This value falls in the neutral zone and does not support benign clinical-history evidence. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BP5 uses multifactorial clinical-history LR thresholds.
Evidence considered
- Clinical-history LR = 0.7760849145466545.
- N_Probands = 1.
- BP5 requires LR ≤0.48 for Supporting strength.
Sources
Not assessed · 7 · no assessment recorded
PS1 No previously established pathogenic BRCA2 variant producing the same amino acid substitution was identified in the reviewed sources, so PS1 was not adjudicated from the available evidence. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PS1 requires the same amino acid substitution as a previously classified pathogenic or likely pathogenic variant, or the same proven splicing effect.
Evidence considered
- ClinVar contains this specific variant but no reviewed evidence in the available materials established a different nucleotide change with the same amino acid consequence for PS1 use.
Still missing
- A dedicated same-amino-acid substitution review was not identified in the available evidence.
Sources
PS4 No case-control comparison or quantified enrichment in affected individuals versus controls was identified from the available evidence, so PS4 was not adjudicated. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PS4 requires significantly increased prevalence in affected individuals compared with controls.
Evidence considered
- ClinVar reports prior clinical observations
- but the available evidence did not provide a qualifying ENIGMA PS4 case-control analysis.
Still missing
- No odds ratio or p-value meeting the ENIGMA PS4 thresholds was identified.
Sources
PM3 No evidence was identified for this variant in trans with another BRCA2 variant in an individual with BRCA2-related Fanconi anemia, so PM3 was not adjudicated. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PM3 is reserved for qualifying biallelic Fanconi anemia contexts.
Evidence considered
- No BRCA2-related Fanconi anemia evidence was provided for this variant.
Still missing
- No qualifying recessive disease or phase data were identified.
Sources
PP1 No quantitative co-segregation data were identified for this variant, so PP1 was not adjudicated. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PP1 requires quantitative co-segregation evidence with LR thresholds.
Evidence considered
- No segregation dataset for this variant was provided.
Still missing
- No family segregation likelihood ratio was identified.
Sources
PP3 SpliceAI predicts no significant splice impact for this variant (max delta score 0.07), which is below the ENIGMA PP3 splice threshold of 0.20. Although residue 3076 lies within the BRCA2 DNA-binding region, no BayesDel no-AF score was identified in the available evidence to complete the ENIGMA missense PP3 rule. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PP3 requires qualifying BayesDel and/or SpliceAI thresholds.
Evidence considered
- SpliceAI max delta score = 0.07.
- ENIGMA BRCA2 PP3 for missense variants inside a clinically important domain requires BayesDel no-AF ≥0.30
- and PP3 for splicing requires SpliceAI ≥0.20.
Still missing
- No BayesDel no-AF score was identified for ENIGMA missense PP3 adjudication.
Sources
BS2 No qualifying observations in individuals without features of BRCA2-related Fanconi anemia were identified to score BS2. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BS2 requires specified point-based evidence in the absence of recessive disease features.
Evidence considered
- No BS2-qualifying clinical observations were provided.
Still missing
- No ENIGMA Table 8 BS2 point-based evidence was identified.
Sources
BS4 No quantitative evidence showing lack of segregation with disease was identified for this variant, so BS4 was not adjudicated. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BS4 requires quantitative lack-of-segregation evidence with LR thresholds.
Evidence considered
- No family non-segregation dataset for this variant was provided.
Still missing
- No non-segregation likelihood ratio was identified.
Sources
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PS2 N/ADe novo evidence is not an applicable ENIGMA BRCA2 criterion in this framework. Details ▾Hide ▴
Rule
Not applicable in ENIGMA BRCA2 v1.2.0.
Evidence considered
- The ENIGMA BRCA2 CSPEC marks PS2 as not applicable.
Sources
PM1 N/APM1 is not used in the ENIGMA BRCA2 framework. Details ▾Hide ▴
Rule
Not applicable in ENIGMA BRCA2 v1.2.0.
Evidence considered
- The ENIGMA BRCA2 CSPEC marks PM1 as not applicable.
Sources
PM4 N/APM4 is not used in the ENIGMA BRCA2 framework. Details ▾Hide ▴
Rule
Not applicable in ENIGMA BRCA2 v1.2.0.
Evidence considered
- The ENIGMA BRCA2 CSPEC marks PM4 as not applicable.
Sources
PM5 N/AIn the ENIGMA BRCA2 framework, PM5 is defined here for protein-truncating variants in eligible exons. This variant is missense, so PM5 is not applicable. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PM5 in this specification is used for qualifying PTC variants, not missense variants.
Evidence considered
- The reviewed ENIGMA PM5 framework is specific to PTC variants for BRCA2.
Sources
cspec ↗vcep_specifications_table4_v1_2_2024_11_18
PM6 N/AAssumed de novo occurrence without confirmed parentage is not an applicable ENIGMA BRCA2 criterion in this framework. Details ▾Hide ▴
Rule
Not applicable in ENIGMA BRCA2 v1.2.0.
Evidence considered
- The ENIGMA BRCA2 CSPEC marks PM6 as not applicable.
Sources
PP2 N/APP2 is not used in the ENIGMA BRCA2 framework. Details ▾Hide ▴
Rule
Not applicable in ENIGMA BRCA2 v1.2.0.
Evidence considered
- The ENIGMA BRCA2 CSPEC marks PP2 as not applicable.
Sources
BP2 N/ABP2 is not used in the ENIGMA BRCA2 framework. Details ▾Hide ▴
Rule
Not applicable in ENIGMA BRCA2 v1.2.0.
Evidence considered
- The ENIGMA BRCA2 CSPEC marks BP2 as not applicable.
Sources
BP3 N/ABP3 is not used in the ENIGMA BRCA2 framework. Details ▾Hide ▴
Rule
Not applicable in ENIGMA BRCA2 v1.2.0.
Evidence considered
- The ENIGMA BRCA2 CSPEC marks BP3 as not applicable.
Sources
BP6 N/ABP6 is not used in the ENIGMA BRCA2 framework. Details ▾Hide ▴
Rule
Not applicable in ENIGMA BRCA2 v1.2.0.
Evidence considered
- The ENIGMA BRCA2 CSPEC marks BP6 as not applicable.
Sources
BP7 N/ABP7 in this framework is for silent or specified intronic variants, whereas NM_000059.4:c.9227G>T is a missense variant. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BP7 is limited to qualifying silent or intronic variants and specific RNA evidence scenarios.
Evidence considered
- The variant is p.(Gly3076Val)
- a missense change.
- SpliceAI does not convert this missense variant into a BP7-eligible silent or intronic context.
Sources
Identifiers
- Gene
- BRCA2
- Transcript
- NM_000059.4
- Coding (HGVS c.)
- NM_000059.4:c.9227G>T
- Protein (HGVS p.)
- NP_000050.3: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_000059.4. 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
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
BP4 SpliceAI predicts no significant splice impact for this variant (max delta score 0.07, below the BP4 splice threshold of 0.10), but ENIGMA BP4 for a missense variant inside a clinically important domain also requires BayesDel no-AF less than or equal to 0.18 and no predicted impact via protein change. Those benign missense conditions were not met from the available evidence, and calibrated functional data support a damaging effect. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BP4 requires benign computational evidence under the specification thresholds.
Evidence considered
- SpliceAI max delta score = 0.07.
- The variant lies in the BRCA2 DNA-binding domain.
- ENIGMA Table 9 supports a damaging functional effect.
Still missing
- No BayesDel no-AF score supporting BP4 was identified.
Sources
PP3 SpliceAI predicts no significant splice impact for this variant (max delta score 0.07), which is below the ENIGMA PP3 splice threshold of 0.20. Although residue 3076 lies within the BRCA2 DNA-binding region, no BayesDel no-AF score was identified in the available evidence to complete the ENIGMA missense PP3 rule. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PP3 requires qualifying BayesDel and/or SpliceAI thresholds.
Evidence considered
- SpliceAI max delta score = 0.07.
- ENIGMA BRCA2 PP3 for missense variants inside a clinically important domain requires BayesDel no-AF ≥0.30
- and PP3 for splicing requires SpliceAI ≥0.20.
Still missing
- No BayesDel no-AF score was identified for ENIGMA missense PP3 adjudication.
Sources
BP7 N/ABP7 in this framework is for silent or specified intronic variants, whereas NM_000059.4:c.9227G>T is a missense variant. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BP7 is limited to qualifying silent or intronic variants and specific RNA evidence scenarios.
Evidence considered
- The variant is p.(Gly3076Val)
- a missense change.
- SpliceAI does not convert this missense variant into a BP7-eligible silent or intronic context.
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
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_000059.4%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).
Functional
OncoKB classifies this variant as Likely Oncogenic; biological effect: Likely Loss-of-function.
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.