About BRCA2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRCA2 c.7879A>T, p.(Ile2627Phe)
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: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PS3Strong
PS3 · strong
This variant has calibrated functional evidence showing a damaging effect on BRCA2 protein function. ENIGMA Table 9 assigns PS3 Strong for c.7879A>T (p.Ile2627Phe), with three calibrated studies reported as supportive of abnormal protein function.
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: Uncertain significance
Official ClinGen ENIGMA BRCA1 and BRCA2 Specification v1.2 Table 3 final-classification combination rules were used as the primary CSPEC/VCEP 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
4 / 1,614,168 alleles
gnomAD v4.1: 4 / 1,614,168 alleles. Recorded AF 2.47806e-06. 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.
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: 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: 2 met · 9 not met · 9 not assessed · 8 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.7879A>T (p.Ile2627Phe) variant has been observed in somatic cancer once in COSMIC and has been reported in ClinVar as Pathogenic, including review by the ClinGen ENIGMA BRCA1/2 expert panel.
This variant is absent from gnomAD v2.1 and present at very low frequency in gnomAD v4.1 at 4/1614168 alleles (AF 2.47806e-06; 0 homozygotes; grpmax FAF 7.9e-07), which is well below benign population thresholds but does not satisfy ENIGMA absence-based PM2.
Calibrated functional evidence supports a damaging effect on BRCA2 protein function, and ENIGMA Table 9 assigns PS3 Strong for c.7879A>T (p.Ile2627Phe).
The variant lies within the BRCA2 DNA-binding domain, while SpliceAI predicts no significant splice effect with a maximum delta score of 0.07.
No criteria match.
Met · 2
PS3 StrongThis variant has calibrated functional evidence showing a damaging effect on BRCA2 protein function. ENIGMA Table 9 assigns PS3 Strong for c.7879A>T (p.Ile2627Phe), with three calibrated studies reported as supportive of abnormal protein function. Details ▾Hide ▴
Rule
Apply PS3 for well-established functional studies supportive of a damaging effect.
Evidence considered
- ENIGMA Table 9 row for BRCA2 c.7879A>T / p.(Ile2627Phe): PS3 Strong
- Table 9 notes three calibrated studies supportive of damaging protein function
- OncoKB lists the variant as Likely Oncogenic with loss-of-function effect
Sources
vcep_specifications_table9_v1_2_2024_11_18oncokb ↗
Not met · 9 · evaluated, threshold not reached
PVS1 This variant is a missense substitution, not a nonsense, frameshift, canonical splice-site, initiation-codon, or exon-level loss-of-function variant, so PVS1 is not met for this BRCA2 change. Details ▾Hide ▴
Rule
PVS1 applies to qualifying loss-of-function variants or qualifying RNA loss-of-function evidence, not to this missense substitution.
Evidence considered
- NM_000059.4:c.7879A>T encodes p.(Ile2627Phe)
- Generic PVS1 scaffold states this variant is not in a default null-variant bucket
- BRCA2 is PVS1-eligible at the gene level
- but this specific variant class does not qualify
Sources
PM2 This variant is absent from gnomAD v2.1 but present in gnomAD v4.1 at 4/1,614,168 alleles (AF 2.47806e-06; 0 homozygotes), so it is not absent from control datasets and PM2 is not met. Details ▾Hide ▴
Rule
ENIGMA PM2 requires absence from control population datasets.
Evidence considered
- gnomAD v2.1: absent
- gnomAD v4.1: 4/1614168 alleles
- AF 2.47806e-06
- grpmax FAF 7.9e-07
- 0 homozygotes
Sources
PP4 The BRCA2 clinical-history likelihood ratio for this variant is 0.68 from 3 probands, which is below the PP4 Supporting threshold of 2.08, so PP4 is not met. Details ▾Hide ▴
Rule
PP4 requires a clinical-history likelihood ratio at or above the ENIGMA threshold.
Evidence considered
- Clinical-history LR = 0.6815268075541039
- N_Probands = 3
- PP4 Supporting threshold >=2.08
Sources
BA1 The gnomAD v4.1 grpmax filter allele frequency is 7.9e-07, which is below the BA1 threshold of 0.001 (0.1%), so BA1 is not met. Details ▾Hide ▴
Rule
BA1 requires population frequency above the stand-alone benign threshold.
Evidence considered
- gnomAD v4.1 grpmax FAF = 7.9e-07
- BA1 threshold = 0.001
Sources
BS1 The gnomAD v4.1 grpmax filter allele frequency is 7.9e-07, which is below the BS1 Supporting threshold of 0.00002 and well below the BS1 Strong threshold of 0.0001, so BS1 is not met. Details ▾Hide ▴
Rule
BS1 requires population frequency above the ENIGMA benign threshold.
Evidence considered
- gnomAD v4.1 grpmax FAF = 7.9e-07
- BS1 Supporting threshold >0.00002
- BS1 Strong threshold >0.0001
Sources
BS3 Available calibrated functional evidence does not show normal BRCA2 protein function. Instead, ENIGMA Table 9 assigns PS3 Strong for damaging functional results, so BS3 is not met. Details ▾Hide ▴
Rule
BS3 requires well-established functional studies showing no damaging effect.
Evidence considered
- ENIGMA Table 9 assigns PS3 Strong rather than BS3
- Functional evidence supports abnormal protein function
Sources
vcep_specifications_table9_v1_2_2024_11_18
BP1 This missense variant is within the BRCA2 DNA-binding domain (amino acids 2481-3186), so it does not meet the BP1 requirement for a missense or silent variant outside a clinically important domain. SpliceAI is low at 0.07, but the domain requirement is not satisfied. Details ▾Hide ▴
Rule
BP1_Strong requires a qualifying variant outside the defined BRCA2 clinically important domains and no predicted splice impact.
Evidence considered
- Protein position 2627 lies within BRCA2 DNA-binding domain aa2481-3186
- SpliceAI max delta score 0.07
Sources
BP5 The BRCA2 clinical-history likelihood ratio for this variant is 0.68 from 3 probands, which is above the BP5 Supporting threshold of 0.48, so BP5 is not met. Details ▾Hide ▴
Rule
BP5 requires a clinical-history likelihood ratio at or below the ENIGMA benign threshold.
Evidence considered
- Clinical-history LR = 0.6815268075541039
- N_Probands = 3
- BP5 Supporting threshold <=0.48
Sources
BP7 Although mRNA evidence in ENIGMA Table 9 notes no aberration and SpliceAI is low at 0.07, this is a missense variant within the BRCA2 DNA-binding domain, and BRCA2 BP7 for missense variants in a clinically important domain requires BS3 to be met. Because functional evidence supports PS3 Strong rather than BS3, BP7 is not met. Details ▾Hide ▴
Rule
BP7 for missense variants in a clinically important BRCA2 domain requires qualifying RNA evidence and BS3.
Evidence considered
- Table 9 notes no aberration on RNA assessment
- SpliceAI max delta score 0.07
- Variant lies in BRCA2 DNA-binding domain aa2481-3186
- BS3 is not met because calibrated functional evidence is damaging
Sources
Not assessed · 9 · no assessment recorded
PS1 No same-amino-acid pathogenic comparison variant was identified in the retrieved evidence, so PS1 was not independently assessed. Details ▾Hide ▴
Rule
PS1 requires an established qualifying comparator variant.
Evidence considered
- Variant is a missense change p.(Ile2627Phe)
- PS1 requires a previously classified pathogenic or likely pathogenic comparator with the same amino-acid consequence or same splicing effect
Still missing
- No curated same-amino-acid pathogenic comparator was identified in the reviewed materials.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
PS4 This variant has been reported in ClinVar and once in COSMIC, and ENIGMA supplementary material lists a posterior pathogenicity of 0.9977 with IARC class 5. However, the retrieved materials do not cleanly separate prevalence-in-affected evidence from other multifactorial components for independent PS4 assignment, so PS4 was not applied in this pass. Details ▾Hide ▴
Rule
PS4 requires prevalence in affected individuals clearly attributable to this criterion.
Evidence considered
- ClinVar expert panel classification: Pathogenic
- COSMIC somatic count: 1
- Supplementary table row for c.7879A>T shows posterior probability 0.9977 and IARC class 5
Still missing
- No directly adjudicable case-control odds ratio and p-value were identified.
- The multifactorial posterior evidence was not separable into a standalone PS4-only component.
Sources
PM3 No evidence was identified for biallelic BRCA2 disease, Fanconi anemia phenotype, or a qualifying in-trans co-occurring BRCA2 pathogenic variant, so PM3 was not assessed. Details ▾Hide ▴
Rule
PM3 requires qualifying recessive-disease observations with in-trans BRCA2 variants.
Evidence considered
- No PM3-relevant proband-level evidence in the reviewed materials
Still missing
- No qualifying recessive-disease or in-trans co-occurrence evidence was identified.
Sources
PM5 No qualifying alternate pathogenic missense variant at the same codon was identified in the retrieved evidence, and the exon-level PM5_PTC framework is for protein-truncating variants rather than this missense substitution, so PM5 was not assessed. Details ▾Hide ▴
Rule
PM5 requires a qualifying same-codon pathogenic comparator or PTC-specific context not present here.
Evidence considered
- Variant is missense
- not protein-truncating
- Reviewed materials did not identify a qualifying alternate pathogenic missense at codon 2627
Still missing
- No curated same-codon alternate pathogenic missense comparator was identified.
Sources
PP1 No quantitative co-segregation likelihood ratio was identified, so PP1 was not assessed. Details ▾Hide ▴
Rule
PP1 requires quantitative co-segregation evidence.
Evidence considered
- No PP1-relevant segregation evidence in the reviewed materials
Still missing
- No family segregation likelihood ratio data were identified.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
PP3 This missense variant lies within the BRCA2 DNA-binding domain, but SpliceAI predicts no significant splice effect (max delta score 0.07, below the PP3 splice threshold of 0.2). The official BRCA2 missense PP3 rule also requires BayesDel no-AF at or above 0.30, and that score was not identified in the retrieved evidence, so PP3 was not independently applied. Details ▾Hide ▴
Rule
PP3 for BRCA2 missense variants requires domain location plus BayesDel no-AF >=0.30, or SpliceAI >=0.2 for splice prediction.
Evidence considered
- Protein position 2627 lies within BRCA2 DNA-binding domain aa2481-3186
- SpliceAI max delta score 0.07
Still missing
- BayesDel no-AF score for this variant was not identified in the reviewed materials.
Sources
BS2 No qualifying observations of this variant in individuals without Fanconi anemia features were identified for BRCA2 BS2 scoring, so BS2 was not assessed. Details ▾Hide ▴
Rule
BS2 requires qualifying observations under the BRCA2 point-based framework.
Evidence considered
- No BS2-relevant proband data in the reviewed materials
Still missing
- No BS2 point-based proband observations were identified.
Sources
BS4 No quantitative lack-of-segregation likelihood ratio was identified, so BS4 was not assessed. Details ▾Hide ▴
Rule
BS4 requires quantitative lack-of-segregation evidence.
Evidence considered
- No BS4-relevant segregation evidence in the reviewed materials
Still missing
- No family lack-of-segregation likelihood ratio data were identified.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
BP4 SpliceAI predicts no significant splice impact (max delta score 0.07, within the BP4 splice threshold of 0.1), and the variant is within the BRCA2 DNA-binding domain. However, the official BRCA2 missense BP4 rule also requires BayesDel no-AF at or below 0.18, and that score was not identified in the retrieved evidence, so BP4 was not independently applied. Details ▾Hide ▴
Rule
BP4 for BRCA2 missense variants inside a clinically important domain requires BayesDel no-AF <=0.18 and SpliceAI <=0.1.
Evidence considered
- Protein position 2627 lies within BRCA2 DNA-binding domain aa2481-3186
- SpliceAI max delta score 0.07
Still missing
- BayesDel no-AF score for this variant was not identified in the reviewed materials.
Sources
Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴
PS2 N/ANo de novo data were identified, and this criterion is not applied in the BRCA2 ENIGMA framework used here. Details ▾Hide ▴
Rule
PS2 is not applicable in this framework.
Evidence considered
- No de novo evidence in the retrieved materials
Sources
PM1 N/APM1 is not applied as a separate criterion in the BRCA2 ENIGMA framework because domain-based missense interpretation is incorporated into the PP3/BP4 bioinformatic rules. Details ▾Hide ▴
Rule
PM1 is not used independently in this framework.
Evidence considered
- BRCA2 specification marks PM1 not applicable and folds domain context into bioinformatic assessment
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
PM4 N/AThis criterion is not applicable in the BRCA2 ENIGMA framework used here. Details ▾Hide ▴
Rule
PM4 is not applicable in this framework.
Evidence considered
- Framework marks PM4 not applicable
Sources
PM6 N/AThis criterion is not applicable in the BRCA2 ENIGMA framework used here. Details ▾Hide ▴
Rule
PM6 is not applicable in this framework.
Evidence considered
- Framework marks PM6 not applicable
Sources
PP2 N/AThis criterion is not applicable in the BRCA2 ENIGMA framework used here. Details ▾Hide ▴
Rule
PP2 is not applicable in this framework.
Evidence considered
- Framework marks PP2 not applicable
Sources
BP2 N/AThis criterion is not applicable in the BRCA2 ENIGMA framework used here. Details ▾Hide ▴
Rule
BP2 is not applicable in this framework.
Evidence considered
- Framework marks BP2 not applicable
Sources
BP3 N/AThis criterion is not applicable in the BRCA2 ENIGMA framework used here. Details ▾Hide ▴
Rule
BP3 is not applicable in this framework.
Evidence considered
- Framework marks BP3 not applicable
Sources
BP6 N/AThis criterion is not applicable in the BRCA2 ENIGMA framework used here. Details ▾Hide ▴
Rule
BP6 is not applicable in this framework.
Evidence considered
- Framework marks BP6 not applicable
Sources
Identifiers
- Gene
- BRCA2
- Transcript
- NM_000059.4
- Coding (HGVS c.)
- NM_000059.4:c.7879A>T
- Protein (HGVS p.)
- NP_000050.3:p.(Ile2627Phe)
- GRCh38
- chr13:32362596 A>T
- GRCh37
- chr13:32936733 A>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
4 / 1,614,168 alleles
AF 2.48e-06 · 0 homozygotes · FAF 7.9e-07
gnomAD v2.1
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 2.5e-06 · 4 / 1,614,168 alleles · 0 hom · FAF 7.9e-07
| European (non-Finnish)4 / 1,180,020 | 3.4e-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.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 2.47806e-06; MAF= 0.00025%, 4/1614168 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.38977e-06; MAF= 0.00034%, 4/1180020 alleles, homozygotes = 0); grpmax FAF= 7.9e-07.
gnomAD v2.1
Absent from gnomAD v2.1.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP7 Although mRNA evidence in ENIGMA Table 9 notes no aberration and SpliceAI is low at 0.07, this is a missense variant within the BRCA2 DNA-binding domain, and BRCA2 BP7 for missense variants in a clinically important domain requires BS3 to be met. Because functional evidence supports PS3 Strong rather than BS3, BP7 is not met. Details ▾Hide ▴
Rule
BP7 for missense variants in a clinically important BRCA2 domain requires qualifying RNA evidence and BS3.
Evidence considered
- Table 9 notes no aberration on RNA assessment
- SpliceAI max delta score 0.07
- Variant lies in BRCA2 DNA-binding domain aa2481-3186
- BS3 is not met because calibrated functional evidence is damaging
Sources
PP3 This missense variant lies within the BRCA2 DNA-binding domain, but SpliceAI predicts no significant splice effect (max delta score 0.07, below the PP3 splice threshold of 0.2). The official BRCA2 missense PP3 rule also requires BayesDel no-AF at or above 0.30, and that score was not identified in the retrieved evidence, so PP3 was not independently applied. Details ▾Hide ▴
Rule
PP3 for BRCA2 missense variants requires domain location plus BayesDel no-AF >=0.30, or SpliceAI >=0.2 for splice prediction.
Evidence considered
- Protein position 2627 lies within BRCA2 DNA-binding domain aa2481-3186
- SpliceAI max delta score 0.07
Still missing
- BayesDel no-AF score for this variant was not identified in the reviewed materials.
Sources
BP4 SpliceAI predicts no significant splice impact (max delta score 0.07, within the BP4 splice threshold of 0.1), and the variant is within the BRCA2 DNA-binding domain. However, the official BRCA2 missense BP4 rule also requires BayesDel no-AF at or below 0.18, and that score was not identified in the retrieved evidence, so BP4 was not independently applied. Details ▾Hide ▴
Rule
BP4 for BRCA2 missense variants inside a clinically important domain requires BayesDel no-AF <=0.18 and SpliceAI <=0.1.
Evidence considered
- Protein position 2627 lies within BRCA2 DNA-binding domain aa2481-3186
- SpliceAI max delta score 0.07
Still missing
- BayesDel no-AF score for this variant was not identified in the reviewed materials.
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
4 / 1,614,168 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/52430/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/13-32936733-A-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr13-32362596-A-T?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000059.4%3Ac.7879…
- OncoKB ↗www.oncokb.org/gene/BRCA2/I2627F
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=123601682
- 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= 2.47806e-06; MAF= 0.00025%, 4/1614168 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.38977e-06; MAF= 0.00034%, 4/1180020 alleles, homozygotes = 0); grpmax FAF= 7.9e-07.
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant has been reported in ClinVar as Pathogenic (20 clinical laboratories) and as Likely pathogenic (2 clinical laboratories) and as pathogenic (1 clinical laboratory) and as Uncertain significance (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: Loss-of-function.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV107497848, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.