About BRCA2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRCA2 c.8164A>G, p.(Thr2722Ala)
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 a calibrated BRCA2 functional dataset, this variant was reported to show protein function similar to pathogenic control variants, and the ENIGMA BRCA2 Table 9 assigns PS3 at strong strength for c.8164A>G (p.Thr2722Ala). This supports a damaging effect on protein function.
PP3Supporting
PP3 · supporting
This missense variant lies within the BRCA2 DNA-binding domain and has a BayesDel no-AF score of 0.396861, which is above the ENIGMA PP3 threshold of 0.30. SpliceAI predicts low splice impact with a maximum delta score of 0.01, so the computational evidence supports a damaging protein effect rather than a splice effect.
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/BRCA2 Specification v1.2 Table 3 criteria-combination framework (CSPEC/VCEP override 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 / 1,614,208 alleles
gnomAD v4.1: 1 / 1,614,208 alleles. Recorded AF 6.19499e-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 · 8 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.8164A>G (p.Thr2722Ala) variant has not been observed in COSMIC and has been reported in ClinVar as Likely Pathogenic, including expert-panel review by ClinGen ENIGMA BRCA1/2.
This variant is absent from gnomAD v2.1 and present once in gnomAD v4.1 (1/1614208 alleles; AF 6.19e-07), supporting that it is very rare in population databases.
In a calibrated BRCA2 functional study, this variant showed protein function similar to pathogenic control variants, and the ENIGMA BRCA2 functional table assigns PS3 at strong strength for p.Thr2722Ala.
This missense change lies within the BRCA2 DNA-binding domain, has a BayesDel no-AF score of 0.396861 above the ENIGMA PP3 threshold of 0.30, and has low predicted splice impact by SpliceAI (maximum delta score 0.01).
No criteria match.
Met · 3
PS3 StrongIn a calibrated BRCA2 functional dataset, this variant was reported to show protein function similar to pathogenic control variants, and the ENIGMA BRCA2 Table 9 assigns PS3 at strong strength for c.8164A>G (p.Thr2722Ala). This supports a damaging effect on protein function. Details ▾Hide ▴
Rule
ENIGMA BRCA2 v1.2 Table 9 calibrated functional evidence
Evidence considered
- Table 9 exact match: BRCA2 c.8164A>G p.(Thr2722Ala) -> PS3 Strong.
- Richardson 2021 listed as damaging.
Sources
PP3 SupportingThis missense variant lies within the BRCA2 DNA-binding domain and has a BayesDel no-AF score of 0.396861, which is above the ENIGMA PP3 threshold of 0.30. SpliceAI predicts low splice impact with a maximum delta score of 0.01, so the computational evidence supports a damaging protein effect rather than a splice effect. Details ▾Hide ▴
Rule
ENIGMA BRCA2 v1.2 PP3 for missense variants in a clinically important domain with BayesDel no-AF >= 0.30
Evidence considered
- Protein position 2722 is within the BRCA2 DNA-binding domain aa 2481-3186.
- BayesDel no-AF = 0.396861.
- SpliceAI max delta score = 0.01.
Sources
Not met · 8 · evaluated, threshold not reached
PVS1 This variant is a missense substitution, not a nonsense, frameshift, or canonical +/-1,2 splice variant, and available data do not show an RNA-only loss-of-function effect. SpliceAI predicts low splice impact with a maximum delta score of 0.01, so available evidence does not support PVS1. Details ▾Hide ▴
Rule
ENIGMA BRCA2 v1.2 PVS1 applies to null variants or qualifying RNA-only loss-of-function evidence.
Evidence considered
- BRCA2 is PVS1-eligible at the gene level
- but this variant is outside the default null-variant buckets.
- SpliceAI max delta score = 0.01.
Sources
PS1 No previously classified pathogenic or likely pathogenic variant with the same amino acid change or the same predicted splice effect was identified in the available evidence, so PS1 is not met. Details ▾Hide ▴
Rule
ENIGMA BRCA2 v1.2 PS1
Evidence considered
- PS1 requires a previously classified pathogenic or likely pathogenic comparator with the same protein or splice consequence.
Still missing
- A directly curated same-amino-acid or same-splice-effect comparator was not identified in the reviewed materials.
Sources
BA1 Population frequency does not meet the benign stand-alone threshold. This variant is absent from gnomAD v2.1 and present once in gnomAD v4.1 (AF 6.19e-07), which is far below the ENIGMA BA1 threshold of filter allele frequency greater than 0.001. Details ▾Hide ▴
Rule
ENIGMA BRCA2 v1.2 BA1
Evidence considered
- gnomAD v4.1 total AF = 6.19498850210134e-07.
Sources
BS1 Population frequency does not meet the ENIGMA BS1 thresholds. This variant is absent from gnomAD v2.1 and present once in gnomAD v4.1 (AF 6.19e-07), which is far below the supporting threshold of filter allele frequency greater than 0.00002 and the strong threshold of greater than 0.0001. Details ▾Hide ▴
Rule
ENIGMA BRCA2 v1.2 BS1
Evidence considered
- gnomAD v4.1 total AF = 6.19498850210134e-07.
Sources
BS3 Available functional evidence does not support a benign effect. Instead, the calibrated ENIGMA BRCA2 functional table assigns PS3_Strong for this exact variant, so BS3 is not met. Details ▾Hide ▴
Rule
ENIGMA BRCA2 v1.2 BS3
Evidence considered
- Exact variant is assigned PS3 Strong in ENIGMA Table 9.
Sources
BP1 This missense variant is located within the BRCA2 DNA-binding domain, so it does not meet the ENIGMA BP1 rule, which is restricted to missense or similar variants outside clinically important functional domains with no predicted splice impact. Details ▾Hide ▴
Rule
ENIGMA BRCA2 v1.2 BP1_Strong
Evidence considered
- Protein position 2722 is within the BRCA2 DNA-binding domain.
- SpliceAI max delta score = 0.01.
Sources
BP4 This variant does not meet the ENIGMA BP4 rule because it is a missense change in the BRCA2 DNA-binding domain and its BayesDel no-AF score is 0.396861, which is above the benign threshold of 0.18. SpliceAI predicts low splice impact (max delta score 0.01), but the protein-based computational evidence does not support a benign interpretation. Details ▾Hide ▴
Rule
ENIGMA BRCA2 v1.2 BP4
Evidence considered
- BayesDel no-AF = 0.396861.
- SpliceAI max delta score = 0.01.
Sources
BP7 This is a missense variant within a clinically important BRCA2 functional domain, and no benign RNA evidence was identified. Available functional evidence instead supports a damaging effect, so BP7 is not met. Details ▾Hide ▴
Rule
ENIGMA BRCA2 v1.2 BP7
Evidence considered
- SpliceAI max delta score = 0.01.
- Exact variant is assigned PS3 Strong in ENIGMA Table 9.
Sources
Not assessed · 8 · no assessment recorded
PS4 Available evidence does not provide a case-control analysis or a quantitative demonstration that this variant is significantly enriched in affected individuals relative to controls, so PS4 cannot be assigned from the reviewed data. Details ▾Hide ▴
Rule
ENIGMA BRCA2 v1.2 PS4 requires significant enrichment in affected individuals.
Evidence considered
- ClinVar reports the variant
- but case-control enrichment evidence was not available.
- No exact variant row was identified in the reviewed local PS4-oriented structured resources.
Still missing
- No variant-specific case-control study with odds ratio and confidence interval was identified.
- No exact multifactorial posterior or case-enrichment record for this variant was identified in the reviewed structured tables.
Sources
PM2 This variant is absent from gnomAD v2.1 and present once in gnomAD v4.1 (1/1614208 alleles; AF 6.19e-07), which is consistent with rarity. However, the ENIGMA BRCA2 PM2 rule is defined against absence in gnomAD v2.1 and v3.1 with adequate coverage, and a v3.1-specific assessment was not available here, so PM2 was not formally assigned. Details ▾Hide ▴
Rule
ENIGMA BRCA2 v1.2 PM2_Supporting
Evidence considered
- gnomAD v2.1 absent.
- gnomAD v4.1 total AF = 6.19498850210134e-07
- AC = 1
- AN = 1614208.
Still missing
- A gnomAD v3.1 non-cancer absence and coverage assessment was not available.
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 was not assessed. Details ▾Hide ▴
Rule
ENIGMA BRCA2 v1.2 PM3
Evidence considered
- ENIGMA BRCA2 PM3 is restricted to BRCA2-related Fanconi anemia scenarios.
Still missing
- No Fanconi anemia phenotype data or confirmed in-trans observations were identified.
Sources
PP1 No segregation data were identified for this variant, so there is no quantitative likelihood ratio to support PP1. Details ▾Hide ▴
Rule
ENIGMA BRCA2 v1.2 PP1
Evidence considered
- PP1 in ENIGMA requires quantitative segregation evidence.
Still missing
- No informative family segregation data or cosegregation likelihood ratio was identified.
Sources
PP4 No variant-specific clinical-history likelihood ratio meeting ENIGMA PP4 thresholds was identified in the reviewed BRCA2 clinical-history resource, so PP4 was not assigned. Details ▾Hide ▴
Rule
ENIGMA BRCA2 v1.2 PP4
Evidence considered
- ENIGMA PP4 requires a quantitative multifactorial clinical-history likelihood ratio.
Still missing
- No exact variant-level PP4 likelihood ratio was identified in the reviewed BRCA2 clinical-history table.
Sources
BS2 No evidence was identified to score this variant in individuals without features of BRCA2-related Fanconi anemia under the ENIGMA point-based BS2 framework, so BS2 was not assessed. Details ▾Hide ▴
Rule
ENIGMA BRCA2 v1.2 BS2
Evidence considered
- ENIGMA BS2 for BRCA2 uses a recessive-disease point framework.
Still missing
- No BS2 point-generating observations were identified.
Sources
BS4 No lack-of-segregation data or quantitative non-segregation likelihood ratio was identified for this variant, so BS4 was not assigned. Details ▾Hide ▴
Rule
ENIGMA BRCA2 v1.2 BS4
Evidence considered
- ENIGMA BS4 requires a quantitative non-segregation likelihood ratio.
Still missing
- No informative family non-segregation data were identified.
Sources
cspec ↗vcep_supplementarytables_v1_2_2024_11_18vcep_humu_40_1557_s001vcep_pmid_17924331_easton_2007_ajhgPMID:17924331 ↗
BP5 No variant-specific clinical-history likelihood ratio meeting ENIGMA BP5 thresholds was identified in the reviewed BRCA2 clinical-history resource, so BP5 was not assigned. Details ▾Hide ▴
Rule
ENIGMA BRCA2 v1.2 BP5
Evidence considered
- ENIGMA BP5 requires a quantitative multifactorial clinical-history likelihood ratio.
Still missing
- No exact variant-level BP5 likelihood ratio was identified in the reviewed BRCA2 clinical-history table.
Sources
Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴
PS2 N/AThis criterion is not applicable in the BRCA2 ENIGMA specification. Details ▾Hide ▴
Rule
Not applicable per ENIGMA BRCA2 v1.2
Evidence considered
- CSPEC marks PS2 as not applicable.
Sources
PM1 N/AThis criterion is not applicable in the BRCA2 ENIGMA specification. Details ▾Hide ▴
Rule
Not applicable per ENIGMA BRCA2 v1.2
Evidence considered
- CSPEC marks PM1 as not applicable.
Sources
PM4 N/AThis criterion is not applicable in the BRCA2 ENIGMA specification. Details ▾Hide ▴
Rule
Not applicable per ENIGMA BRCA2 v1.2
Evidence considered
- CSPEC marks PM4 as not applicable.
Sources
PM5 N/AFor BRCA2 in this specification, PM5 is repurposed for protein-truncating variant logic rather than classic same-residue missense comparison. Because this variant is a missense substitution, PM5 is not applicable. Details ▾Hide ▴
Rule
ENIGMA BRCA2 v1.2 PM5_PTC framework
Evidence considered
- pm5_candidates.json indicates PM5 mode = ptc_gene_specific and classic same-residue missense PM5 is not eligible.
Sources
PM6 N/AThis criterion is not applicable in the BRCA2 ENIGMA specification. Details ▾Hide ▴
Rule
Not applicable per ENIGMA BRCA2 v1.2
Evidence considered
- CSPEC marks PM6 as not applicable.
Sources
PP2 N/AThis criterion is not applicable in the BRCA2 ENIGMA specification. Details ▾Hide ▴
Rule
Not applicable per ENIGMA BRCA2 v1.2
Evidence considered
- CSPEC marks PP2 as not applicable.
Sources
BP2 N/AThis criterion is not applicable in the BRCA2 ENIGMA specification. Details ▾Hide ▴
Rule
Not applicable per ENIGMA BRCA2 v1.2
Evidence considered
- CSPEC marks BP2 as not applicable.
Sources
BP3 N/AThis criterion is not applicable in the BRCA2 ENIGMA specification. Details ▾Hide ▴
Rule
Not applicable per ENIGMA BRCA2 v1.2
Evidence considered
- CSPEC marks BP3 as not applicable.
Sources
BP6 N/AThis criterion is not applicable in the BRCA2 ENIGMA specification. Details ▾Hide ▴
Rule
Not applicable per ENIGMA BRCA2 v1.2
Evidence considered
- CSPEC marks BP6 as not applicable.
Sources
Identifiers
- Gene
- BRCA2
- Transcript
- NM_000059.3
- Coding (HGVS c.)
- NM_000059.3:c.8164A>G
- Protein (HGVS p.)
- NP_000050.2:p.(Thr2722Ala)
- GRCh38
- chr13:32363366 A>G
- GRCh37
- chr13:32937503 A>G
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 / 1,614,208 alleles
AF 6.19e-07 · 0 homozygotes
gnomAD v2.1
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 6.2e-07 · 1 / 1,614,208 alleles · 0 hom
| European (non-Finnish)1 / 1,180,030 | 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= 6.19499e-07; MAF= 0.00006%, 1/1614208 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47436e-07; MAF= 0.00008%, 1/1180030 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 and has a BayesDel no-AF score of 0.396861, which is above the ENIGMA PP3 threshold of 0.30. SpliceAI predicts low splice impact with a maximum delta score of 0.01, so the computational evidence supports a damaging protein effect rather than a splice effect. Details ▾Hide ▴
Rule
ENIGMA BRCA2 v1.2 PP3 for missense variants in a clinically important domain with BayesDel no-AF >= 0.30
Evidence considered
- Protein position 2722 is within the BRCA2 DNA-binding domain aa 2481-3186.
- BayesDel no-AF = 0.396861.
- SpliceAI max delta score = 0.01.
Sources
BP4 This variant does not meet the ENIGMA BP4 rule because it is a missense change in the BRCA2 DNA-binding domain and its BayesDel no-AF score is 0.396861, which is above the benign threshold of 0.18. SpliceAI predicts low splice impact (max delta score 0.01), but the protein-based computational evidence does not support a benign interpretation. Details ▾Hide ▴
Rule
ENIGMA BRCA2 v1.2 BP4
Evidence considered
- BayesDel no-AF = 0.396861.
- SpliceAI max delta score = 0.01.
Sources
BP7 This is a missense variant within a clinically important BRCA2 functional domain, and no benign RNA evidence was identified. Available functional evidence instead supports a damaging effect, so BP7 is not met. Details ▾Hide ▴
Rule
ENIGMA BRCA2 v1.2 BP7
Evidence considered
- SpliceAI max delta score = 0.01.
- Exact variant is assigned PS3 Strong in ENIGMA Table 9.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.827. BayesDel score = 0.396861.
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 / 1,614,208 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/479367/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/13-32937503-A-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr13-32363366-A-G?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000059.3%3Ac.8164…
- OncoKB ↗www.oncokb.org/gene/BRCA2/T2722A
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=BRCA2+c.8164A%3EG
- 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= 6.19499e-07; MAF= 0.00006%, 1/1614208 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47436e-07; MAF= 0.00008%, 1/1180030 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 Likely Pathogenic by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 479367)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.827. BayesDel score = 0.396861.
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.