About BRCA2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRCA2 c.2820A>G, p.(Gln940=)
Classification
Likely benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely benign. Select a step to read what it means.
Likely benign.A likely 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: 2
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 2
BP1Strong
BP1 · strong
This is a synonymous BRCA2 variant, p.(Gln940=), located outside the clinically important BRCA2 domains defined by ENIGMA (PALB2-binding aa 10-40 and DNA-binding aa 2481-3186), and SpliceAI predicts no splice effect with a maximum delta score of 0.00, which is below the <=0.10 threshold. This meets BP1_Strong.
BP6Supporting
BP6 · supporting
Expert panel Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) classified as Likely benign.
Recorded classification: Likely benign
ENIGMA BRCA1/BRCA2 Specification v1.2 Table 3 final-classification framework (official CSPEC/VCEP criteria-combination rules).
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 / 1,613,806 alleles
gnomAD v4.1: 1 / 1,613,806 alleles. Recorded AF 6.19653e-07. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.98979e-06; MAF= 0.00040%, 1/250640 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 5.43833e-05; MAF= 0.00544%, 1/18388 alleles, homozygotes = 0).
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 oncogenicity for this specific variant: Unknown Oncogenic Effect (variant has not been individually curated).
No listed criterion applied
OncoKB ↗
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 · 4 not met · 11 not assessed · 11 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 NM_000059.4:c.2820A>G (p.(Gln940=), p.(Q940=)) variant has been reported in ClinVar as likely benign, including review by the ENIGMA expert panel and multiple clinical laboratories.
This variant is present at very low frequency in population databases, with 1/250640 alleles in gnomAD v2.1 (AF 0.00040%) and 1/1613806 alleles in gnomAD v4.1 (AF 0.00006%), which does not meet ENIGMA benign stand-alone or strong population thresholds and does not satisfy PM2 absence criteria.
In silico splicing analysis predicts no significant splice impact, with a SpliceAI maximum delta score of 0.00, and the synonymous p.(Gln940=) change lies outside the BRCA2 clinically important domains defined by ENIGMA, supporting BP1_Strong and arguing against PP3.
No criteria match.
Met · 2
BP1 StrongThis is a synonymous BRCA2 variant, p.(Gln940=), located outside the clinically important BRCA2 domains defined by ENIGMA (PALB2-binding aa 10-40 and DNA-binding aa 2481-3186), and SpliceAI predicts no splice effect with a maximum delta score of 0.00, which is below the <=0.10 threshold. This meets BP1_Strong. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BP1_Strong applies to silent substitutions outside clinically important domains with SpliceAI <= 0.10.
Evidence considered
- Protein consequence p.(Gln940=).
- Codon 940 lies outside aa 10-40 and aa 2481-3186.
- SpliceAI max delta score 0.00.
Sources
BP6 SupportingExpert panel Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) classified as Likely benign. Details ▾Hide ▴
Not met · 4 · evaluated, threshold not reached
PM2 This variant is not absent from population databases, so PM2 is not met. It is present in gnomAD v2.1 at 1/250640 alleles (AF 0.00040%) and in gnomAD v4.1 at 1/1613806 alleles (AF 0.00006%). Details ▾Hide ▴
Rule
ENIGMA BRCA2 PM2_Supporting requires absence from gnomAD controls.
Evidence considered
- gnomAD v2.1 total AF 3.989786147462496e-06.
- gnomAD v4.1 total AF 6.196531677289588e-07.
Sources
PP3 Available computational evidence does not support a splice-altering effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, which is below the ENIGMA PP3 threshold of 0.20. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PP3 for splicing requires SpliceAI >= 0.20.
Evidence considered
- SpliceAI DS_AG 0.00
- DS_AL 0.00
- DS_DG 0.00
- DS_DL 0.00
- max delta score 0.00.
Sources
BA1 This variant does not meet the ENIGMA BA1 population threshold. It is seen only once in gnomAD v2.1 (AF 0.00040%) and once in gnomAD v4.1 (AF 0.00006%), both well below the BA1 threshold of 0.1%. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BA1 requires filter allele frequency > 0.1%.
Evidence considered
- gnomAD v2.1 total AF 0.00040%.
- gnomAD v4.1 total AF 0.00006%.
Sources
BS1 Available population data do not support BS1. The variant is observed only once in gnomAD v2.1 and once in gnomAD v4.1, and no population frequency above the ENIGMA BS1 thresholds was identified. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BS1 requires filter allele frequency above 0.002% for Supporting or above 0.01% for Strong in non-founder populations.
Evidence considered
- gnomAD v2.1 total AF 0.00040%
- highest observed East Asian AF 0.00544%.
- gnomAD v4.1 total AF 0.00006%
- highest observed East Asian AF 0.00223%.
Sources
Not assessed · 11 · no assessment recorded
PS1 No evidence was identified that this variant has the same proven pathogenic protein or splicing consequence as a previously classified pathogenic BRCA2 variant, so PS1 was not assessed further. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PS1 requires the same proven pathogenic protein or splicing consequence as a previously classified variant.
Evidence considered
- SpliceAI max delta score 0.00 does not indicate a predicted splice-altering effect.
Still missing
- No validated reference pathogenic variant with the same established splice effect was identified.
Sources
PS3 No variant-specific damaging functional study meeting the ENIGMA BRCA2 PS3 framework was identified for this variant. Details ▾Hide ▴
Rule
PS3 requires well-established functional evidence supportive of a damaging effect.
Evidence considered
- ENIGMA Table 9 search found no exact c.2820A>G or p.(Gln940=) entry.
Still missing
- No exact entry for NM_000059.4:c.2820A>G was identified in ENIGMA Table 9 functional assay results.
Sources
vcep_specifications_table9_v1_2_2024_11_18cspec ↗
PS4 No case-control or multifactorial evidence was identified showing this variant is significantly enriched in affected individuals compared with controls. Details ▾Hide ▴
Rule
PS4 requires increased prevalence in affected individuals compared with controls.
Evidence considered
- No exact c.2820A>G or p.(Gln940=) entry was identified in the reviewed ENIGMA supplementary tables or Parsons dataset.
Still missing
- No exact variant entry was identified in the reviewed ENIGMA supplementary or multifactorial BRCA resources for PS4 assessment.
Sources
PM3 No evidence was identified for occurrence with another BRCA2 variant in a phenotype consistent with BRCA2-related Fanconi anemia, so PM3 was not assessed further. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PM3 is reserved for recessive Fanconi anemia presentations with qualifying co-occurrence data.
Still missing
- No Fanconi anemia or phase data were identified.
Sources
PP1 No quantitative segregation data were identified for this variant, so PP1 was not assessed. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PP1 requires quantitative co-segregation evidence.
Still missing
- No family segregation likelihood ratio was identified.
Sources
PP4 No variant-specific multifactorial clinical-history likelihood ratio supporting pathogenicity was identified for this variant, so PP4 was not assessed. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PP4 requires a qualifying clinical-history LR >= 2.08.
Evidence considered
- Exact HGVS lookup in the BRCA2 clinical-history LR table found no c.2820A>G entry.
Still missing
- No exact NM_000059.4:c.2820A>G entry was identified in the BRCA2 clinical-history likelihood-ratio table.
Sources
vcep_pmid_31853058_brca2_clinical_history_lrcspec ↗
BS2 No evidence was identified showing occurrence in individuals without features of BRCA2-related Fanconi anemia sufficient for ENIGMA BS2 scoring. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BS2 requires point-based evidence from individuals lacking recessive disease features.
Still missing
- No qualifying proband-level BS2 point data were identified.
Sources
BS3 No variant-specific benign functional study meeting the ENIGMA BRCA2 BS3 framework was identified for this variant. Details ▾Hide ▴
Rule
BS3 requires well-established functional evidence showing no damaging effect.
Evidence considered
- ENIGMA Table 9 search found no exact c.2820A>G or p.(Gln940=) entry.
Still missing
- No exact entry for NM_000059.4:c.2820A>G was identified in ENIGMA Table 9 functional assay results.
Sources
vcep_specifications_table9_v1_2_2024_11_18cspec ↗
BS4 No quantitative lack-of-segregation evidence was identified for this variant, so BS4 was not assessed. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BS4 requires quantitative lack-of-segregation evidence.
Evidence considered
- No exact variant entry was identified in the reviewed ENIGMA supplementary or multifactorial BRCA resources for segregation-based assessment.
Still missing
- No segregation likelihood ratio supporting BS4 was identified.
Sources
BP5 No variant-specific multifactorial clinical-history likelihood ratio supporting a benign interpretation was identified for this variant, so BP5 was not assessed. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BP5 requires a qualifying clinical-history LR <= 0.48.
Evidence considered
- Exact HGVS lookup in the BRCA2 clinical-history LR table found no c.2820A>G entry.
Still missing
- No exact NM_000059.4:c.2820A>G entry was identified in the BRCA2 clinical-history likelihood-ratio table.
Sources
vcep_pmid_31853058_brca2_clinical_history_lrcspec ↗
BP7 SpliceAI predicts no splice impact, but no qualifying RNA study showing a benign transcript outcome was identified for this variant, so BP7 was not assessed beyond computational evidence alone. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BP7 generally requires qualifying RNA evidence, or a silent-variant/domain scenario not met here.
Evidence considered
- SpliceAI max delta score 0.00.
- No exact c.2820A>G entry identified in reviewed splicing/functional tables.
Still missing
- No variant-specific RNA assay result was identified in the reviewed ENIGMA BRCA resources.
Sources
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis synonymous variant does not create a premature stop, frameshift, or canonical +/-1,2 splice-site change, so the BRCA2 PVS1 loss-of-function framework does not apply. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PVS1 applies to null variants or qualifying RNA evidence, which are not present here.
Evidence considered
- BRCA2 loss of function is an established disease mechanism in the ENIGMA framework.
- NM_000059.4:c.2820A>G is a synonymous exon 11 variant with no canonical splice-site alteration.
Sources
PS2 N/ADe novo occurrence is not part of the ENIGMA BRCA2 framework for this review. Details ▾Hide ▴
Rule
Not applicable in ENIGMA BRCA2 specification.
Evidence considered
- CSPEC marks PS2 as not applicable.
Sources
PM1 N/APM1 is not used in the ENIGMA BRCA2 specification for this review. Details ▾Hide ▴
Rule
Not applicable in ENIGMA BRCA2 specification.
Evidence considered
- CSPEC marks PM1 as not applicable.
Sources
PM4 N/APM4 does not apply because this is not a protein length-changing variant, and the ENIGMA BRCA2 specification marks PM4 as not applicable. Details ▾Hide ▴
Rule
Not applicable in ENIGMA BRCA2 specification.
Evidence considered
- CSPEC marks PM4 as not applicable.
Sources
PM5 N/APM5 in the ENIGMA BRCA2 framework is used for missense changes or protein-truncating variants in qualifying exons, which does not fit this synonymous variant. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PM5 does not apply to this synonymous substitution.
Evidence considered
- Variant consequence is synonymous p.(Gln940=).
Sources
PM6 N/AAssumed de novo occurrence without confirmed parentage is not part of the ENIGMA BRCA2 framework for this review. Details ▾Hide ▴
Rule
Not applicable in ENIGMA BRCA2 specification.
Evidence considered
- CSPEC marks PM6 as not applicable.
Sources
PP2 N/APP2 is not used in the ENIGMA BRCA2 specification for this review. Details ▾Hide ▴
Rule
Not applicable in ENIGMA BRCA2 specification.
Evidence considered
- CSPEC marks PP2 as not applicable.
Sources
PP5 N/APP5 is not used in the ENIGMA BRCA2 specification for this review. Details ▾Hide ▴
Rule
Not applicable in ENIGMA BRCA2 specification.
Evidence considered
- CSPEC marks PP5 as not applicable.
Sources
BP2 N/ABP2 is not used in the ENIGMA BRCA2 specification for this review. Details ▾Hide ▴
Rule
Not applicable in ENIGMA BRCA2 specification.
Evidence considered
- CSPEC marks BP2 as not applicable.
Sources
BP3 N/ABP3 is not used in the ENIGMA BRCA2 specification for this review. Details ▾Hide ▴
Rule
Not applicable in ENIGMA BRCA2 specification.
Evidence considered
- CSPEC marks BP3 as not applicable.
Sources
BP4 N/AENIGMA BP4 for silent variants is limited to synonymous changes inside a clinically important domain with no predicted splice effect. This synonymous variant is outside the defined BRCA2 clinically important domains, so BP4 does not apply. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BP4 silent-variant rule is restricted to clinically important domains.
Evidence considered
- Protein position 940 is outside aa 10-40 and aa 2481-3186.
- SpliceAI max delta score 0.00.
Sources
Identifiers
- Gene
- BRCA2
- Transcript
- NM_000059.4
- Coding (HGVS c.)
- NM_000059.4:c.2820A>G
- Protein (HGVS p.)
- NP_000050.3:p.(Gln940=)
- GRCh38
- chr13:32337175 A>G
- GRCh37
- chr13:32911312 A>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
1 / 1,613,806 alleles
AF 6.2e-07 · 0 homozygotes
gnomAD v2.1
1 / 250,640 alleles
AF 3.99e-06 · 0 homozygotes
By genetic ancestry
gnomAD v4.1
AF 6.2e-07 · 1 / 1,613,806 alleles · 0 hom
| East Asian1 / 44,830 | 2.2e-05 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish).
gnomAD v2.1
AF 4e-06 · 1 / 250,640 alleles · 0 hom
| East Asian1 / 18,388 | 5.4e-05 |
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, European (Finnish), European (non-Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 6.19653e-07; MAF= 0.00006%, 1/1613806 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 2.23065e-05; MAF= 0.00223%, 1/44830 alleles, homozygotes = 0).
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.98979e-06; MAF= 0.00040%, 1/250640 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 5.43833e-05; MAF= 0.00544%, 1/18388 alleles, homozygotes = 0).
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 Available computational evidence does not support a splice-altering effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, which is below the ENIGMA PP3 threshold of 0.20. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PP3 for splicing requires SpliceAI >= 0.20.
Evidence considered
- SpliceAI DS_AG 0.00
- DS_AL 0.00
- DS_DG 0.00
- DS_DL 0.00
- max delta score 0.00.
Sources
BP7 SpliceAI predicts no splice impact, but no qualifying RNA study showing a benign transcript outcome was identified for this variant, so BP7 was not assessed beyond computational evidence alone. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BP7 generally requires qualifying RNA evidence, or a silent-variant/domain scenario not met here.
Evidence considered
- SpliceAI max delta score 0.00.
- No exact c.2820A>G entry identified in reviewed splicing/functional tables.
Still missing
- No variant-specific RNA assay result was identified in the reviewed ENIGMA BRCA resources.
Sources
BP4 N/AENIGMA BP4 for silent variants is limited to synonymous changes inside a clinically important domain with no predicted splice effect. This synonymous variant is outside the defined BRCA2 clinically important domains, so BP4 does not apply. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BP4 silent-variant rule is restricted to clinically important domains.
Evidence considered
- Protein position 940 is outside aa 10-40 and aa 2481-3186.
- 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
1 / 1,613,806 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/427526/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/13-32911312-A-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr13-32337175-A-G?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000059.4%3Ac.2820…
- OncoKB ↗www.oncokb.org/gene/BRCA2/Q940=
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=BRCA2+c.2820A%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= 6.19653e-07; MAF= 0.00006%, 1/1613806 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 2.23065e-05; MAF= 0.00223%, 1/44830 alleles, homozygotes = 0).
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.98979e-06; MAF= 0.00040%, 1/250640 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 5.43833e-05; MAF= 0.00544%, 1/18388 alleles, homozygotes = 0).
ClinVar
This variant has been reported in ClinVar as Likely benign (6 clinical laboratories) and as Likely Benign (1 clinical laboratory) and as Likely benign by Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) (expert panel).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional
OncoKB oncogenicity for this specific variant: Unknown Oncogenic Effect (variant has not been individually curated).
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.