About BRCA2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRCA2 c.831T>G, p.(Asn277Lys)
Classification
Benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is benign. Select a step to read what it means.
Benign.A benign 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: 0
Benign evidence criteria: 4
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 4
BS1Strong
BS1 · strong
This variant is present in gnomAD at a frequency above the ENIGMA BS1 strong threshold. In gnomAD v2.1, the highest observed filter allele frequency is 0.0001033 in the European (non-Finnish) population, which is above the BS1 strong threshold of 0.0001.
BS3Strong
BS3 · strong
Calibrated functional evidence supports no damaging effect. ENIGMA Table 9 lists c.831T>G (p.(Asn277Lys)) as BS3 Strong because one calibrated study found protein function similar to benign control variants.
BP1Strong
BP1 · strong
This missense variant affects codon 277, which is outside the BRCA2 clinically important domains used by ENIGMA for missense interpretation (PALB2-binding aa 10-40 and DNA-binding aa 2481-3186), and SpliceAI predicts no splice effect with a max delta score of 0.00, which is at or below the BP1 threshold of 0.10. This supports BP1_Strong.
BP6Supporting
BP6 · supporting
Expert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Benign.
Recorded classification: Benign
Official ClinGen/ENIGMA BRCA1/2 final-classification framework used: ENIGMA BRCA1 and BRCA2 Specification v1.2, Table 3 criteria-combination rules via the final_classification_framework 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
303 / 1,606,240 alleles
gnomAD v4.1: 303 / 1,606,240 alleles. Recorded AF 0.000188639. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 6.87096e-05; MAF= 0.00687%, 19/276526 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000149258; MAF= 0.01493%, 19/127296 alleles, homozygotes = 0); grpmax FAF= 0.0001033.
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 has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: BRCA2, a tumor suppressor involved in the DNA damage response, is mutated in various cancer types.
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 · 4 not met · 8 not assessed · 12 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.831T>G (p.Asn277Lys) variant has been reported in ClinVar and is classified as Benign by the ClinGen ENIGMA BRCA1/2 expert panel.
This variant is present in population databases, including gnomAD v2.1 at AF 0.0000687 with a highest observed filter allele frequency of 0.0001033 and gnomAD v4.1 at AF 0.0001886 with a highest observed filter allele frequency of 0.0002296, supporting BS1.
Calibrated functional data in the ENIGMA BRCA1/2 specification support no damaging effect on protein function for p.(Asn277Lys), supporting BS3.
In silico evidence does not suggest splice disruption, with a SpliceAI maximum delta score of 0.00, and the missense change lies outside the BRCA2 clinically important domains used by ENIGMA for missense interpretation, supporting BP1_Strong.
No criteria match.
Met · 4
BS1 StrongThis variant is present in gnomAD at a frequency above the ENIGMA BS1 strong threshold. In gnomAD v2.1, the highest observed filter allele frequency is 0.0001033 in the European (non-Finnish) population, which is above the BS1 strong threshold of 0.0001. Details ▾Hide ▴
Rule
FAF > 0.0001 in a non-founder population
Evidence considered
- gnomAD v2.1 grpmax FAF 0.0001033
- gnomAD v4.1 grpmax FAF 0.0002296
Sources
BS3 StrongCalibrated functional evidence supports no damaging effect. ENIGMA Table 9 lists c.831T>G (p.(Asn277Lys)) as BS3 Strong because one calibrated study found protein function similar to benign control variants. Details ▾Hide ▴
Rule
Calibrated functional study shows no damaging effect
Evidence considered
- ENIGMA Table 9 assignment: BS3 Strong
- Reported as similar to benign controls in one calibrated study
Sources
BP1 StrongThis missense variant affects codon 277, which is outside the BRCA2 clinically important domains used by ENIGMA for missense interpretation (PALB2-binding aa 10-40 and DNA-binding aa 2481-3186), and SpliceAI predicts no splice effect with a max delta score of 0.00, which is at or below the BP1 threshold of 0.10. This supports BP1_Strong. Details ▾Hide ▴
Rule
Missense variant outside clinically important domain and SpliceAI <= 0.1
Evidence considered
- Residue 277 is outside aa 10-40 and aa 2481-3186
- SpliceAI max delta score 0.00
Sources
Not met · 4 · evaluated, threshold not reached
PS3 Available calibrated functional evidence does not support a damaging effect. ENIGMA Table 9 lists this variant as showing protein function similar to benign control variants, so PS3 is not met. Details ▾Hide ▴
Evidence considered
- ENIGMA Table 9 entry for c.831T>G / p.(Asn277Lys) assigns BS3 Strong
Sources
PM2 This variant is not absent from population databases. It is present in gnomAD v2.1 at AF 0.0000687 (19/276526 alleles) and in gnomAD v4.1 at AF 0.0001886 (303/1606240 alleles), so the ENIGMA PM2 absence-from-controls requirement is not met. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 total AF 0.0000687
- gnomAD v4.1 total AF 0.0001886
Sources
PP3 Available predictive evidence does not support a damaging effect under the BRCA2 ENIGMA PP3 rule. This missense variant is outside the ENIGMA clinically important domains, and SpliceAI shows no predicted splice impact with a max delta score of 0.00, which is below the PP3 splice threshold of 0.20. Details ▾Hide ▴
Evidence considered
- Residue 277 is outside BRCA2 aa 10-40 and aa 2481-3186 domains
- SpliceAI max delta score 0.00
Sources
BA1 The population frequency does not meet the ENIGMA BA1 threshold. The highest observed filter allele frequency is 0.0001033 in gnomAD v2.1 and 0.0002296 in gnomAD v4.1, both below the BA1 threshold of 0.001. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 grpmax FAF 0.0001033
- gnomAD v4.1 grpmax FAF 0.0002296
Sources
Not assessed · 8 · no assessment recorded
PS1 No evidence was identified showing that this variant produces the same protein change or the same proven splicing effect as a previously established pathogenic BRCA2 variant. Details ▾Hide ▴
Evidence considered
- ClinVar record reviewed
- SpliceAI max delta score 0.00
Still missing
- No qualifying pathogenic reference variant with the same amino-acid or splicing consequence was identified
Sources
PS4 No standalone case-control evidence was identified showing that this variant is significantly enriched in affected individuals compared with controls at the ENIGMA PS4 threshold. Details ▾Hide ▴
PM3 No evidence was identified of this variant occurring with another BRCA2 variant in a patient with phenotype consistent with BRCA2-related Fanconi anemia, so PM3 cannot be assessed. Details ▾Hide ▴
PP1 No quantitative co-segregation data were identified showing that this variant tracks with disease in affected relatives, so PP1 cannot be applied. Details ▾Hide ▴
Still missing
- No segregation likelihood ratio meeting ENIGMA PP1 thresholds was identified
Sources
PP4 No qualifying multifactorial clinical-history likelihood ratio was identified for this variant, so PP4 cannot be applied. Details ▾Hide ▴
Evidence considered
- BRCA2 clinical-history LR workbook reviewed with no matching entry
Still missing
- No variant-specific entry was identified in the BRCA2 clinical-history LR resource
Sources
BS2 No data were identified showing this variant in individuals without features of BRCA2-related Fanconi anemia in a way that permits ENIGMA BS2 point assignment. Details ▾Hide ▴
Still missing
- No qualifying phenotype and zygosity data for BS2 point assignment were identified
Sources
BS4 No quantitative non-segregation analysis was identified showing lack of segregation with disease at an ENIGMA BS4 likelihood ratio threshold. Details ▾Hide ▴
BP5 No qualifying multifactorial clinical-history likelihood ratio in the benign direction was identified for this variant, so BP5 cannot be applied. Details ▾Hide ▴
Evidence considered
- BRCA2 clinical-history LR workbook reviewed with no matching entry
Still missing
- No variant-specific entry was identified in the BRCA2 clinical-history LR resource
Sources
Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis variant is a missense substitution, p.(Asn277Lys), and does not fall into the BRCA2 loss-of-function variant categories used for PVS1 such as nonsense, frameshift, initiation codon, or canonical +/-1,2 splice site variants. Details ▾Hide ▴
Evidence considered
- Missense variant p.(Asn277Lys)
- Generic PVS1 scaffold did not place this variant in a null-variant bucket
Sources
PS2 N/ANo confirmed de novo occurrence data were identified, and this criterion is not applicable based on the available BRCA2 ENIGMA framework for this case. Details ▾Hide ▴
Sources
PM1 N/APM1 is not applicable in the BRCA2 ENIGMA framework for this case, and this variant is not located in a BRCA2 region used here for PM1-based assertion. Details ▾Hide ▴
PM4 N/AThis variant is a missense substitution and not a protein length-changing in-frame event, so PM4 is not applicable. Details ▾Hide ▴
PM5 N/AIn the BRCA2 ENIGMA framework reviewed for this case, PM5 is used for protein-terminating variant contexts and does not apply to this missense substitution. Details ▾Hide ▴
Evidence considered
- Missense variant p.(Asn277Lys)
Sources
cspec ↗vcep_specifications_table4_v1_2_2024_11_18
PM6 N/ANo assumed or confirmed de novo data were identified, and this criterion is not applicable based on the available BRCA2 ENIGMA framework for this case. Details ▾Hide ▴
Sources
PP2 N/APP2 is not applicable in the BRCA2 ENIGMA framework for this case. Details ▾Hide ▴
Sources
PP5 N/APP5 is not applied in this framework because external assertions alone are not used as independent pathogenic evidence. Details ▾Hide ▴
BP2 N/ANo phased co-occurrence data were identified, and BP2 is not applicable in the BRCA2 ENIGMA framework for this case. Details ▾Hide ▴
Sources
BP3 N/ABP3 is not applicable in the BRCA2 ENIGMA framework for this case. Details ▾Hide ▴
Sources
BP4 N/AUnder the BRCA2 ENIGMA framework, BP4 for missense variants applies within clinically important functional domains with no predicted impact. This variant is outside those domains, so benign missense evidence is captured by BP1_Strong rather than BP4. Details ▾Hide ▴
Evidence considered
- Residue 277 is outside BRCA2 aa 10-40 and aa 2481-3186
- SpliceAI max delta score 0.00
Sources
BP7 N/AThis is a missense variant, not a silent or qualifying intronic variant, and no RNA assay evidence was identified to support BP7-based benign splicing interpretation. Details ▾Hide ▴
Evidence considered
- Missense variant p.(Asn277Lys)
- SpliceAI max delta score 0.00
Sources
Identifiers
- Gene
- BRCA2
- Transcript
- NM_000059.4
- Coding (HGVS c.)
- NM_000059.4:c.831T>G
- Protein (HGVS p.)
- NP_000050.3:p.(Asn277Lys)
- GRCh38
- chr13:32332309 T>G
- GRCh37
- chr13:32906446 T>G
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
303 / 1,606,240 alleles
AF 0.000189 · 0 homozygotes · FAF 0.00023
gnomAD v2.1
19 / 276,526 alleles
AF 6.87e-05 · 0 homozygotes · FAF 0.000103
By genetic ancestry
gnomAD v4.1
AF 0.00019 · 303 / 1,606,240 alleles · 0 hom · FAF 0.00023
| European (non-Finnish)298 / 1,176,744 | 0.00025 |
| Remaining individuals4 / 62,198 | 6.4e-05 |
| African/African American1 / 74,526 | 1.3e-05 |
0 alternate alleles recorded in 7 other groups: Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish.
gnomAD v2.1
AF 6.9e-05 · 19 / 276,526 alleles · 0 hom · FAF 0.0001
| European (non-Finnish)19 / 127,296 | 0.00015 |
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= 0.000188639; MAF= 0.01886%, 303/1606240 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000253241; MAF= 0.02532%, 298/1176744 alleles, homozygotes = 0); grpmax FAF= 0.0002296.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 6.87096e-05; MAF= 0.00687%, 19/276526 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000149258; MAF= 0.01493%, 19/127296 alleles, homozygotes = 0); grpmax FAF= 0.0001033.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 Available predictive evidence does not support a damaging effect under the BRCA2 ENIGMA PP3 rule. This missense variant is outside the ENIGMA clinically important domains, and SpliceAI shows no predicted splice impact with a max delta score of 0.00, which is below the PP3 splice threshold of 0.20. Details ▾Hide ▴
Evidence considered
- Residue 277 is outside BRCA2 aa 10-40 and aa 2481-3186 domains
- SpliceAI max delta score 0.00
Sources
BP4 N/AUnder the BRCA2 ENIGMA framework, BP4 for missense variants applies within clinically important functional domains with no predicted impact. This variant is outside those domains, so benign missense evidence is captured by BP1_Strong rather than BP4. Details ▾Hide ▴
Evidence considered
- Residue 277 is outside BRCA2 aa 10-40 and aa 2481-3186
- SpliceAI max delta score 0.00
Sources
BP7 N/AThis is a missense variant, not a silent or qualifying intronic variant, and no RNA assay evidence was identified to support BP7-based benign splicing interpretation. Details ▾Hide ▴
Evidence considered
- Missense variant p.(Asn277Lys)
- SpliceAI max delta score 0.00
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
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
303 / 1,606,240 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/38152/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/13-32906446-T-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr13-32332309-T-G?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000059.4%3Ac.831T…
- OncoKB ↗www.oncokb.org/gene/BRCA2/N277K
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=BRCA2+c.831T%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= 0.000188639; MAF= 0.01886%, 303/1606240 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000253241; MAF= 0.02532%, 298/1176744 alleles, homozygotes = 0); grpmax FAF= 0.0002296.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 6.87096e-05; MAF= 0.00687%, 19/276526 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000149258; MAF= 0.01493%, 19/127296 alleles, homozygotes = 0); grpmax FAF= 0.0001033.
ClinVar
This variant has been reported in ClinVar as Likely benign (13 clinical laboratories) and as Benign (5 clinical laboratories) and as Uncertain significance (5 clinical laboratories) and as likely benign (1 clinical laboratory) and as Benign 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 = 0.00).
Functional
OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: BRCA2, a tumor suppressor involved in the DNA damage response, is mutated in various cancer types.
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.