About BRCA2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRCA2 c.2353A>G, p.(Ile785Val)
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: 1
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 1
BP1Strong
BP1 · strong
This missense variant is outside the BRCA2 clinically important domains specified by ENIGMA for missense pathogenicity assessment (PALB2-binding aa 10-40; DNA-binding aa 2481-3186), and SpliceAI predicts no splice impact (max delta score 0.00). This supports BP1_Strong.
Recorded classification: Likely benign
Official ENIGMA BRCA1/BRCA2 v1.2 Table 3 final-classification framework was used. The only applied criterion is BP1_Strong, and the framework permits a Likely Benign classification from one strong benign criterion when that code reflects multiple evidence types.
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
19 / 1,613,924 alleles
gnomAD v4.1: 19 / 1,613,924 alleles. Recorded AF 1.17725e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.06298e-05; MAF= 0.00106%, 3/282226 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000139159; MAF= 0.01392%, 1/7186 alleles, homozygotes = 0); grpmax FAF= 1.082e-05.
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.
Context only
ClinVar ↗
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.
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: 1 met · 6 not met · 9 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 NM_000059.4:c.2353A>G (p.(Ile785Val), p.(I785V)) variant has been reported in ClinVar, with predominantly uncertain significance submissions and one likely benign submission.
This variant is present in gnomAD v2.1 at AF 1.06298e-05 (3/282226 alleles) with grpmax FAF 1.082e-05, which is below ENIGMA BA1 and BS1 thresholds and also means the variant is not absent from controls for PM2.
In a published mouse embryonic stem cell-based assay, I785V was reported as functionally indistinguishable from wild-type BRCA2; however, this variant was not identified with a preassigned PS3 or BS3 code in the ENIGMA curated functional table, so the functional evidence remains for manual review.
This missense change lies outside the BRCA2 PALB2-binding and DNA-binding domains used for ENIGMA missense pathogenicity assessment, SpliceAI predicts no splice impact (max delta 0.00), BayesDel is -0.394429, and REVEL is 0.16, supporting BP1_Strong and arguing against PP3.
No criteria match.
Met · 1
BP1 StrongThis missense variant is outside the BRCA2 clinically important domains specified by ENIGMA for missense pathogenicity assessment (PALB2-binding aa 10-40; DNA-binding aa 2481-3186), and SpliceAI predicts no splice impact (max delta score 0.00). This supports BP1_Strong. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BP1_Strong
Evidence considered
- Protein change p.(Ile785Val) is outside aa 10-40 and aa 2481-3186.
- SpliceAI max delta score 0.00.
Sources
Not met · 6 · evaluated, threshold not reached
PS3 A published mouse embryonic stem cell-based assay reported I785V as functionally indistinguishable from wild-type BRCA2, which does not support a damaging functional effect. The variant was also not identified in the ENIGMA curated functional table as a PS3-coded variant. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PS3
Evidence considered
- PMID:32393398 abstract: I785V was functionally indistinguishable from wild type.
- No PS3 assignment for this variant was found in ENIGMA Table 9.
Still missing
- If desired
- the full study methods could be reviewed to determine whether the benign-direction functional evidence is strong enough for BS3 under Figure 1C.
Sources
PS4 No case-control study or ENIGMA multifactorial dataset entry was identified showing a statistically significant enrichment of this variant in affected individuals compared with controls, so PS4 was not met. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PS4
Still missing
- No variant-specific PS4 case-control result was identified in the retrieved materials.
Sources
PM2 This variant is present in gnomAD v2.1 with 3/282226 alleles (AF 1.06298e-05; grpmax FAF 1.082e-05), so it is not absent from controls and does not meet ENIGMA PM2_Supporting. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PM2_Supporting requires absence from controls
Evidence considered
- gnomAD v2.1 total AF 1.0629778971462586e-05.
- gnomAD v2.1 grpmax FAF 1.082e-05.
Still missing
- A matched non-cancer v3.1 lookup was not retrieved
- but presence in gnomAD v2.1 is already sufficient to withhold PM2.
Sources
PP3 This missense change is outside the BRCA2 PALB2-binding domain (aa 10-40) and DNA-binding region (aa 2481-3186) used for ENIGMA missense PP3. SpliceAI predicts no splice effect (max delta score 0.00), BayesDel is -0.394429, and REVEL is 0.16, so the available computational evidence does not support PP3. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PP3 Supporting
Evidence considered
- SpliceAI max delta score 0.00.
- BayesDel no-AF score -0.394429.
- REVEL score 0.16.
Sources
BA1 The gnomAD v2.1 grpmax FAF is 1.082e-05, which is well below the ENIGMA BA1 threshold of 0.001, so BA1 is not met. Details ▾Hide ▴
BS1 The gnomAD v2.1 grpmax FAF is 1.082e-05, which is below the ENIGMA BS1_Supporting threshold of 0.00002 and the BS1 threshold of 0.0001, so BS1 is not met. Details ▾Hide ▴
Not assessed · 9 · no assessment recorded
PS1 No previously classified pathogenic or likely pathogenic reference variant producing the same amino acid change or the same predicted splice effect was identified in the retrieved evidence, so PS1 was not applied. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PS1
Still missing
- A dedicated same-amino-acid-change lookup was not available in the retrieved materials.
Sources
PM3 No evidence was identified that this variant was observed in trans with another BRCA2 variant in a proband with BRCA2-related Fanconi anemia, so PM3 was not applied. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PM3
Still missing
- No Fanconi anemia phenotype or phase data were identified.
Sources
PP1 No quantitative co-segregation data were identified for this variant, so PP1 was not applied. Details ▾Hide ▴
PP4 No variant-specific multifactorial clinical-history likelihood ratio meeting ENIGMA PP4 thresholds was identified, so PP4 was not applied. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PP4
Still missing
- This variant was not identified in the retrieved BRCA2 clinical-history LR workbook.
Sources
BS2 No point-based evidence was identified showing this variant in individuals without features of BRCA2-related Fanconi anemia, so BS2 was not applied. Details ▾Hide ▴
BS3 A published mouse embryonic stem cell-based assay reported I785V as functionally indistinguishable from wild-type BRCA2, which is consistent with a benign effect. However, this variant was not identified in the ENIGMA curated functional table with a preassigned BS3 code, so BS3 was left for manual review rather than applied here. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BS3
Evidence considered
- PMID:32393398 abstract: I785V was functionally indistinguishable from wild type.
- No BS3 assignment for this variant was found in ENIGMA Table 9.
Still missing
- Direct review of the full PMID:32393398 study and ENIGMA Figure 1C calibration framework would be needed to determine whether BS3 can be assigned.
Sources
BS4 No quantitative lack-of-segregation evidence was identified for this variant, so BS4 was not applied. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BS4
Still missing
- No segregation likelihood ratio against pathogenicity was available.
Sources
BP5 No variant-specific multifactorial clinical-history likelihood ratio meeting ENIGMA BP5 thresholds was identified, so BP5 was not applied. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BP5
Still missing
- This variant was not identified in the retrieved BRCA2 clinical-history LR workbook.
Sources
BP7 This is a missense variant, and no RNA study showing a normal transcript outcome was identified. Computational splice prediction alone does not justify BP7 here, so BP7 was not applied. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BP7
Evidence considered
- SpliceAI max delta score 0.00.
Still missing
- No variant-specific RNA assay result was identified.
Sources
Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis missense variant does not fall into the BRCA2 null-variant or splice-consensus categories used for PVS1, and the generic PVS1 scaffold states that it is not a nonsense, frameshift, or canonical ±1,2 splice variant. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PVS1 / generic PVS1 scaffold
Evidence considered
- BRCA2 loss of function is an established disease mechanism in the ENIGMA framework.
- NM_000059.4:c.2353A>G is a missense substitution
- not a null variant.
Sources
PS2 N/AThis criterion is designated not applicable for BRCA2 in the ENIGMA specification. Details ▾Hide ▴
PM1 N/AThis criterion is designated not applicable for BRCA2 in the ENIGMA specification. Details ▾Hide ▴
PM4 N/AThis criterion is designated not applicable for BRCA2 in the ENIGMA specification. Details ▾Hide ▴
PM5 N/AIn the BRCA2 ENIGMA specification, PM5 is used for protein-truncating variants already annotated with PVS1. This missense variant does not fit that use case. Details ▾Hide ▴
PM6 N/AThis criterion is designated not applicable for BRCA2 in the ENIGMA specification. Details ▾Hide ▴
PP2 N/AThis criterion is designated not applicable for BRCA2 in the ENIGMA specification. Details ▾Hide ▴
PP5 N/AThis criterion is designated not applicable for BRCA2 in the ENIGMA specification. Details ▾Hide ▴
BP2 N/AThis criterion is designated not applicable for BRCA2 in the ENIGMA specification. Details ▾Hide ▴
BP3 N/AThis criterion is designated not applicable for BRCA2 in the ENIGMA specification. Details ▾Hide ▴
BP4 N/AFor BRCA2, ENIGMA BP4 applies to missense variants inside specified clinically important domains when BayesDel is ≤0.18 and SpliceAI is ≤0.1. Although this variant has no predicted splice impact (SpliceAI 0.00), a low BayesDel score (-0.394429), and a low REVEL score (0.16), it lies outside the specified domains, so BP4 is not the applicable benign computational code. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BP4 domain-restricted rule
Evidence considered
- SpliceAI max delta score 0.00.
- BayesDel no-AF score -0.394429.
- REVEL score 0.16.
Sources
BP6 N/AThis criterion is designated not applicable for BRCA2 in the ENIGMA specification. Details ▾Hide ▴
Identifiers
- Gene
- BRCA2
- Transcript
- NM_000059.4
- Coding (HGVS c.)
- NM_000059.4:c.2353A>G
- Protein (HGVS p.)
- NP_000050.3:p.(Ile785Val)
- GRCh38
- chr13:32336708 A>G
- GRCh37
- chr13:32910845 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
19 / 1,613,924 alleles
AF 1.18e-05 · 0 homozygotes · FAF 0.000118
gnomAD v2.1
3 / 282,226 alleles
AF 1.06e-05 · 0 homozygotes · FAF 1.08e-05
By genetic ancestry
gnomAD v4.1
AF 1.2e-05 · 19 / 1,613,924 alleles · 0 hom · FAF 0.00012
| South Asian17 / 91,086 | 0.00019 |
| Remaining individuals1 / 62,484 | 1.6e-05 |
| European (non-Finnish)1 / 1,179,960 | 8.5e-07 |
0 alternate alleles recorded in 7 other groups: Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 1.1e-05 · 3 / 282,226 alleles · 0 hom · FAF 1.1e-05
| Remaining individuals1 / 7,186 | 0.00014 |
| South Asian2 / 30,610 | 6.5e-05 |
0 alternate alleles recorded in 6 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish).
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.17725e-05; MAF= 0.00118%, 19/1613924 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000186637; MAF= 0.01866%, 17/91086 alleles, homozygotes = 0); grpmax FAF= 0.00011837.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.06298e-05; MAF= 0.00106%, 3/282226 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000139159; MAF= 0.01392%, 1/7186 alleles, homozygotes = 0); grpmax FAF= 1.082e-05.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 This missense change is outside the BRCA2 PALB2-binding domain (aa 10-40) and DNA-binding region (aa 2481-3186) used for ENIGMA missense PP3. SpliceAI predicts no splice effect (max delta score 0.00), BayesDel is -0.394429, and REVEL is 0.16, so the available computational evidence does not support PP3. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PP3 Supporting
Evidence considered
- SpliceAI max delta score 0.00.
- BayesDel no-AF score -0.394429.
- REVEL score 0.16.
Sources
BP7 This is a missense variant, and no RNA study showing a normal transcript outcome was identified. Computational splice prediction alone does not justify BP7 here, so BP7 was not applied. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BP7
Evidence considered
- SpliceAI max delta score 0.00.
Still missing
- No variant-specific RNA assay result was identified.
Sources
BP4 N/AFor BRCA2, ENIGMA BP4 applies to missense variants inside specified clinically important domains when BayesDel is ≤0.18 and SpliceAI is ≤0.1. Although this variant has no predicted splice impact (SpliceAI 0.00), a low BayesDel score (-0.394429), and a low REVEL score (0.16), it lies outside the specified domains, so BP4 is not the applicable benign computational code. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BP4 domain-restricted rule
Evidence considered
- SpliceAI max delta score 0.00.
- BayesDel no-AF score -0.394429.
- REVEL score 0.16.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.16. BayesDel score = -0.394429.
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
19 / 1,613,924 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/462264/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/13-32910845-A-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr13-32336708-A-G?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000059.4%3Ac.2353…
- OncoKB ↗www.oncokb.org/gene/BRCA2/I785V
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=BRCA2+c.2353A%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= 1.17725e-05; MAF= 0.00118%, 19/1613924 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000186637; MAF= 0.01866%, 17/91086 alleles, homozygotes = 0); grpmax FAF= 0.00011837.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.06298e-05; MAF= 0.00106%, 3/282226 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000139159; MAF= 0.01392%, 1/7186 alleles, homozygotes = 0); grpmax FAF= 1.082e-05.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (5 clinical laboratories) and as Likely benign (1 clinical laboratory) and as Uncertain Significance (1 clinical laboratory).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.16. BayesDel score = -0.394429.
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 not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.