About BRCA2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRCA2 c.7057G>C, p.(Gly2353Arg)
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: 5
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 5
BS1Supporting
BS1 · supporting
This variant meets ENIGMA BS1_Supporting because the filter allele frequency is above 0.00002 and not above 0.0001. The grpmax FAF is 2.859e-05 in gnomAD v2.1 and 8.841e-05 in gnomAD v4.1, both within the BS1_Supporting range.
BS3Strong
BS3 · strong
In a calibrated BRCA2 functional study, this variant showed protein function similar to benign control variants, with complementation observed and an HDR score of 82. ENIGMA Table 9 assigns BS3 Strong for this variant.
BS4Supporting
BS4 · supporting
Available segregation evidence supports lack of segregation with disease. The segregation likelihood ratio is 0.345, which is below the ENIGMA BS4_Supporting threshold of 0.48.
BP1Strong
BP1 · strong
This missense variant is outside the BRCA2 ENIGMA clinically important missense domains and has no predicted splice impact. Residue 2353 lies outside the PALB2 binding domain (aa 10-40) and DNA-binding region (aa 2481-3186), and SpliceAI is 0.01, below the no-splicing-impact threshold of 0.1, so BP1_Strong is met.
BP6Supporting
BP6 · supporting
Expert panel Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) classified as Benign.
Recorded classification: Benign
ENIGMA BRCA1/BRCA2 Specification v1.2 final-classification framework (Table 3 override captured in final_classification_framework; ACMG/AMP 2015 with ENIGMA adaptations).
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
125 / 1,613,500 alleles
gnomAD v4.1: 125 / 1,613,500 alleles. Recorded AF 7.74713e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 4.78332e-05; MAF= 0.00478%, 12/250872 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000491965; MAF= 0.04920%, 3/6098 alleles, homozygotes = 0); grpmax FAF= 2.859e-05.
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 did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. 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: 5 met · 6 not met · 5 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.7057G>C (p.Gly2353Arg) variant has been reported in ClinVar, where the aggregate record includes an ENIGMA expert panel Benign classification.
This variant is present in gnomAD, with grpmax filter allele frequencies of 2.859e-05 in v2.1 and 8.841e-05 in v4.1, which are above the ENIGMA BS1_Supporting threshold of 0.00002 and do not reach the BS1 Strong threshold of 0.0001.
In a calibrated BRCA2 functional study, this variant showed protein function similar to benign control variants, including observed complementation and an HDR score of 82, and ENIGMA Table 9 assigns BS3 Strong.
Computational evidence does not support a damaging effect: SpliceAI predicts no significant splice impact with a max delta score of 0.01, BayesDel no-AF is -0.110167, and codon 2353 lies outside the BRCA2 ENIGMA clinically important missense domains, supporting BP1 rather than PP3.
No criteria match.
Met · 5
BS1 SupportingThis variant meets ENIGMA BS1_Supporting because the filter allele frequency is above 0.00002 and not above 0.0001. The grpmax FAF is 2.859e-05 in gnomAD v2.1 and 8.841e-05 in gnomAD v4.1, both within the BS1_Supporting range. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 grpmax FAF 2.859e-05.
- gnomAD v4.1 grpmax FAF 8.841e-05.
- ENIGMA BS1_Supporting range is FAF >0.00002 and ≤0.0001.
Sources
BS3 StrongIn a calibrated BRCA2 functional study, this variant showed protein function similar to benign control variants, with complementation observed and an HDR score of 82. ENIGMA Table 9 assigns BS3 Strong for this variant. Details ▾Hide ▴
Evidence considered
- ENIGMA Table 9 entry: BS3 Strong for BRCA2 c.7057G>C p.(Gly2353Arg).
- Mesman assay summary: complementation yes
- HDR 82
- no functional impact.
Sources
BS4 SupportingAvailable segregation evidence supports lack of segregation with disease. The segregation likelihood ratio is 0.345, which is below the ENIGMA BS4_Supporting threshold of 0.48. Details ▾Hide ▴
Evidence considered
- Parsons multifactorial dataset segregation LR 0.345.
- ENIGMA BS4_Supporting requires LR ≤0.48.
Sources
vcep_humu_40_1557_s001cspec ↗
BP1 StrongThis missense variant is outside the BRCA2 ENIGMA clinically important missense domains and has no predicted splice impact. Residue 2353 lies outside the PALB2 binding domain (aa 10-40) and DNA-binding region (aa 2481-3186), and SpliceAI is 0.01, below the no-splicing-impact threshold of 0.1, so BP1_Strong is met. Details ▾Hide ▴
Evidence considered
- Protein position 2353 is outside BRCA2 aa 10-40 and aa 2481-3186 ENIGMA domains.
- SpliceAI max delta score 0.01.
- ENIGMA BP1_Strong applies to missense variants outside these domains with SpliceAI ≤0.1.
Sources
Not met · 6 · evaluated, threshold not reached
PS3 Available functional evidence does not support a damaging effect. In a calibrated BRCA2 functional dataset, this variant showed protein function similar to benign control variants, so PS3 is not met. Details ▾Hide ▴
Evidence considered
- ENIGMA Table 9 lists c.7057G>C p.(Gly2353Arg) as BS3 Strong.
- Mesman functional results recorded complementation yes and HDR 82
- interpreted as no functional impact.
Sources
PS4 Available data do not show statistically significant enrichment in affected individuals at the ENIGMA PS4 threshold. No case-control evidence meeting the required significance standard was identified, and the available multifactorial dataset shows a case-control likelihood ratio of 1.88 rather than strong case enrichment. Details ▾Hide ▴
Evidence considered
- Parsons multifactorial dataset lists case-control LR 1.88 for this variant.
- ENIGMA PS4 requires statistically significant enrichment in affected individuals.
Still missing
- No case-control result with p-value ≤0.05 and odds ratio ≥4 was identified.
Sources
PM2 This variant is present in population databases and therefore does not meet ENIGMA PM2, which requires absence from controls. In gnomAD v2.1 the variant has AF 4.78332e-05 with grpmax FAF 2.859e-05, and in gnomAD v4.1 it has AF 7.74713e-05 with grpmax FAF 8.841e-05. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 total AF 4.78332e-05
- grpmax FAF 2.859e-05.
- gnomAD v4.1 total AF 7.74713e-05
- grpmax FAF 8.841e-05.
- ENIGMA PM2 requires absence from gnomAD controls.
Sources
PP1 Available family data do not support co-segregation with disease. The reviewed multifactorial dataset shows a segregation likelihood ratio of 0.345, which is below the PP1 threshold of 2.08 and instead supports BS4. Details ▾Hide ▴
Evidence considered
- Segregation LR 0.345 in the Parsons multifactorial dataset.
- ENIGMA PP1 requires segregation LR ≥2.08.
Sources
vcep_humu_40_1557_s001cspec ↗
PP3 Computational evidence does not support a damaging effect. This residue lies outside the BRCA2 ENIGMA missense functional domains, BayesDel no-AF is -0.110167 which is below the PP3 threshold of 0.30, and SpliceAI predicts no significant splice impact with a max delta score of 0.01, below the PP3 splice threshold of 0.2. Details ▾Hide ▴
Evidence considered
- BayesDel no-AF score -0.110167.
- SpliceAI max delta score 0.01.
- ENIGMA PP3 for missense variants requires location in a defined functional domain plus BayesDel ≥0.30
- or predicted splicing with SpliceAI ≥0.2.
Sources
BA1 The population frequency does not reach the ENIGMA BA1 stand-alone benign threshold. The highest observed grpmax FAF is 8.841e-05 in gnomAD v4.1, which is below the BA1 threshold of 0.001. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 grpmax FAF 2.859e-05.
- gnomAD v4.1 grpmax FAF 8.841e-05.
- ENIGMA BA1 requires FAF >0.001.
Sources
Not assessed · 5 · no assessment recorded
PS1 No evidence was identified showing that this amino acid change is the same protein consequence as a previously established pathogenic BRCA2 variant acting through the protein rather than splicing. Details ▾Hide ▴
Evidence considered
- ClinVar record for this exact variant was reviewed.
- ENIGMA BRCA2 PS1 rules require a previously classified pathogenic or likely pathogenic reference variant with the same relevant consequence.
Still missing
- No validated reference pathogenic variant with the same amino acid substitution was identified in the reviewed sources.
Sources
PM3 No evidence was identified showing this variant in trans with another BRCA2 variant in a patient with BRCA2-related Fanconi anemia, so PM3 could not be applied. Details ▾Hide ▴
Evidence considered
- ENIGMA PM3 is restricted to BRCA1/2-related Fanconi anemia scenarios.
Still missing
- No BRCA2-related Fanconi anemia proband data or trans-phase observations were identified.
Sources
PP4 No approved BRCA2 clinical-history likelihood-ratio result meeting ENIGMA PP4 thresholds was identified for this exact variant in the reviewed clinical-history table. Details ▾Hide ▴
Evidence considered
- The BRCA2 clinical-history LR workbook was reviewed and no exact c.7057G>C entry was identified.
Still missing
- No exact match for this variant was found in the BRCA2 clinical-history LR table used for PP4/BP5.
Sources
BS2 No data were identified showing this variant in sufficient individuals without features of BRCA2-related Fanconi anemia to apply BS2. Details ▾Hide ▴
Evidence considered
- ENIGMA BS2 requires specific proband-level evidence in the absence of recessive disease features.
Still missing
- No BS2 point-based proband data were identified.
Sources
BP5 No approved BRCA2 clinical-history likelihood-ratio result meeting ENIGMA BP5 thresholds was identified for this exact variant in the reviewed clinical-history table. Details ▾Hide ▴
Evidence considered
- The BRCA2 clinical-history LR workbook was reviewed and no exact c.7057G>C entry was identified.
Still missing
- No exact match for this variant was found in the BRCA2 clinical-history LR table used for PP4/BP5.
Sources
Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis missense variant does not fall within the BRCA2 null-variant or canonical splice-site categories used for PVS1, and SpliceAI predicts no significant splice impact (max delta score 0.01). Details ▾Hide ▴
Evidence considered
- BRCA2 is PVS1-eligible at the gene level
- but this variant is not a nonsense
- frameshift
- initiation-codon
- exon-deletion
- or canonical ±1
- 2 splice variant.
- SpliceAI max delta score 0.01 does not support an RNA loss-of-function mechanism.
Sources
PS2 N/AThe BRCA2 ENIGMA specification does not use PS2 for this gene-specific framework. Details ▾Hide ▴
PM1 N/APM1 is not used in the BRCA2 ENIGMA specification for this framework. Details ▾Hide ▴
PM4 N/APM4 is not used in the BRCA2 ENIGMA specification for this framework. Details ▾Hide ▴
PM5 N/AIn the BRCA2 ENIGMA specification, PM5 is used for protein-truncating variants in eligible exons rather than for this missense substitution. Details ▾Hide ▴
Evidence considered
- This variant is missense
- not a protein-truncating variant.
- ENIGMA BRCA2 PM5 guidance is PTC-focused.
Sources
cspec ↗vcep_specifications_table4_v1_2_2024_11_18
PM6 N/AThe BRCA2 ENIGMA specification does not use PM6 for this gene-specific framework. Details ▾Hide ▴
PP2 N/APP2 is not used in the BRCA2 ENIGMA specification for this framework. Details ▾Hide ▴
PP5 N/APP5 is not used in current ACMG/AMP interpretation under this framework. Details ▾Hide ▴
BP2 N/ABP2 is not used in the BRCA2 ENIGMA specification for this framework. Details ▾Hide ▴
BP3 N/ABP3 is not used in the BRCA2 ENIGMA specification for this framework. Details ▾Hide ▴
BP4 N/ABP4 is not the applicable benign computational criterion for this variant under the BRCA2 ENIGMA framework. For missense variants outside the defined functional domains with no splice impact, the specification directs use of BP1 rather than BP4. Details ▾Hide ▴
Evidence considered
- BayesDel no-AF score -0.110167.
- SpliceAI max delta score 0.01.
- ENIGMA BP4 missense rule is limited to variants inside defined functional domains.
Sources
BP7 N/ABP7 is not applicable because this is a missense variant rather than a silent or intronic variant in the BP7 evidence framework. Details ▾Hide ▴
Evidence considered
- The variant changes glycine to arginine at codon 2353.
- ENIGMA BP7 guidance is directed to silent
- intronic
- and selected RNA-only contexts.
Sources
Identifiers
- Gene
- BRCA2
- Transcript
- NM_000059.4
- Coding (HGVS c.)
- NM_000059.4:c.7057G>C
- Protein (HGVS p.)
- NP_000050.3:p.(Gly2353Arg)
- GRCh38
- chr13:32354910 G>C
- GRCh37
- chr13:32929047 G>C
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
125 / 1,613,500 alleles
AF 7.75e-05 · 0 homozygotes · FAF 8.84e-05
gnomAD v2.1
12 / 250,872 alleles
AF 4.78e-05 · 0 homozygotes · FAF 2.86e-05
By genetic ancestry
gnomAD v4.1
AF 7.7e-05 · 125 / 1,613,500 alleles · 0 hom · FAF 8.8e-05
| European (non-Finnish)122 / 1,179,768 | 0.0001 |
| African/African American2 / 74,856 | 2.7e-05 |
| Admixed American1 / 59,970 | 1.7e-05 |
0 alternate alleles recorded in 7 other groups: Remaining individuals, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish.
gnomAD v2.1
AF 4.8e-05 · 12 / 250,872 alleles · 0 hom · FAF 2.9e-05
| Remaining individuals3 / 6,098 | 0.00049 |
| African/African American1 / 16,144 | 6.2e-05 |
| European (non-Finnish)7 / 113,486 | 6.2e-05 |
| Admixed American1 / 34,518 | 2.9e-05 |
0 alternate alleles recorded in 4 other groups: Ashkenazi Jewish, East Asian, European (Finnish), South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 7.74713e-05; MAF= 0.00775%, 125/1613500 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.00010341; MAF= 0.01034%, 122/1179768 alleles, homozygotes = 0); grpmax FAF= 8.841e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 4.78332e-05; MAF= 0.00478%, 12/250872 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000491965; MAF= 0.04920%, 3/6098 alleles, homozygotes = 0); grpmax FAF= 2.859e-05.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 Computational evidence does not support a damaging effect. This residue lies outside the BRCA2 ENIGMA missense functional domains, BayesDel no-AF is -0.110167 which is below the PP3 threshold of 0.30, and SpliceAI predicts no significant splice impact with a max delta score of 0.01, below the PP3 splice threshold of 0.2. Details ▾Hide ▴
Evidence considered
- BayesDel no-AF score -0.110167.
- SpliceAI max delta score 0.01.
- ENIGMA PP3 for missense variants requires location in a defined functional domain plus BayesDel ≥0.30
- or predicted splicing with SpliceAI ≥0.2.
Sources
BP4 N/ABP4 is not the applicable benign computational criterion for this variant under the BRCA2 ENIGMA framework. For missense variants outside the defined functional domains with no splice impact, the specification directs use of BP1 rather than BP4. Details ▾Hide ▴
Evidence considered
- BayesDel no-AF score -0.110167.
- SpliceAI max delta score 0.01.
- ENIGMA BP4 missense rule is limited to variants inside defined functional domains.
Sources
BP7 N/ABP7 is not applicable because this is a missense variant rather than a silent or intronic variant in the BP7 evidence framework. Details ▾Hide ▴
Evidence considered
- The variant changes glycine to arginine at codon 2353.
- ENIGMA BP7 guidance is directed to silent
- intronic
- and selected RNA-only contexts.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.4. BayesDel score = -0.110167.
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
125 / 1,613,500 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/52260/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/13-32929047-G-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr13-32354910-G-C?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000059.4%3Ac.7057…
- OncoKB ↗www.oncokb.org/gene/BRCA2/G2353R
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=123597896
- 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= 7.74713e-05; MAF= 0.00775%, 125/1613500 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.00010341; MAF= 0.01034%, 122/1179768 alleles, homozygotes = 0); grpmax FAF= 8.841e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 4.78332e-05; MAF= 0.00478%, 12/250872 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000491965; MAF= 0.04920%, 3/6098 alleles, homozygotes = 0); grpmax FAF= 2.859e-05.
ClinVar
This variant has been reported in ClinVar as Likely benign (11 clinical laboratories) and as Benign (7 clinical laboratories) and as Uncertain significance (4 clinical laboratories) and as likely benign (1 clinical laboratory) and as 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 = 0.01). REVEL score = 0.4. BayesDel score = -0.110167.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. 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 previously been reported in somatic cancers (COSMIC; COSV99061638, n = 3 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.