About BRCA2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRCA2 c.4757C>T, p.(Thr1586Ile)
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: 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 functional domains used by ENIGMA for missense interpretation, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, meeting BP1_Strong.
Recorded classification: Uncertain significance
Official BRCA2 ENIGMA/ClinGen final-classification framework using ACMG/AMP 2015 with ENIGMA Table 3 adaptations and no qualifying additional benign or pathogenic combination beyond BP1_Strong.
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 / 1,613,958 alleles
gnomAD v4.1: 1 / 1,613,958 alleles. Recorded AF 6.19595e-07. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
No listed criterion applied
SpliceAI score
0.010 maximum delta
Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
1 reported laboratory submissions
1 Likely benign.
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
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
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 · 5 not met · 10 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.4757C>T (p.Thr1586Ile) variant has been reported in ClinVar as likely benign by one clinical laboratory.
This variant is absent from gnomAD v2.1 and gnomAD-Canada and is present only once in gnomAD v4.1 (1/1,613,958 alleles; AF 6.20e-07), which is far below ENIGMA benign frequency thresholds but does not meet the requirement for complete absence from controls.
No variant-specific functional assay result for p.(Thr1586Ile) was identified in the reviewed BRCA2 ENIGMA functional resources.
Computational evidence does not support a damaging effect: p.(Thr1586Ile) lies outside the BRCA2 clinically important domains used for ENIGMA missense interpretation, SpliceAI shows a maximum delta score of 0.01, BayesDel no-AF is -0.443818, and REVEL is 0.182, supporting BP1_Strong and not supporting PP3.
No criteria match.
Met · 1
BP1 StrongThis missense variant is outside the BRCA2 clinically important functional domains used by ENIGMA for missense interpretation, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, meeting BP1_Strong. Details ▾Hide ▴
Rule
BP1_Strong applies to missense variants outside clinically important domains with SpliceAI ≤0.1.
Evidence considered
- p.(Thr1586Ile) is outside aa 10-40 and aa 2481-3186 domains
- SpliceAI max delta 0.01
Sources
Not met · 5 · evaluated, threshold not reached
PVS1 This missense variant does not create a premature termination codon, frameshift, or canonical ±1,2 splice-site change, so the BRCA2 PVS1 framework is not met. Details ▾Hide ▴
Rule
PVS1 applies to null variants or qualifying RNA evidence under the BRCA2 ENIGMA specification.
Evidence considered
- NM_000059.4:c.4757C>T encodes p.(Thr1586Ile)
- generic PVS1 scaffold marks the variant outside null-variant buckets
Sources
PM2 This variant is absent from gnomAD v2.1 and gnomAD-Canada, but it is present in gnomAD v4.1 at 1/1,613,958 alleles (AF 6.20e-07; highest population AF 8.48e-07 in European non-Finnish), so the criterion for absence from controls is not met. Details ▾Hide ▴
Rule
PM2_Supporting requires absence from controls in the ENIGMA BRCA2 framework.
Evidence considered
- gnomAD v2.1 absent
- gnomAD v4.1 total AF 6.195948097781974e-07 (1/1613958)
- gnomAD-Canada absent
Sources
PP3 Computational evidence does not support a damaging effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, BayesDel no-AF is -0.443818, and p.(Thr1586Ile) lies outside the BRCA2 clinically important domains used for missense PP3 application. Details ▾Hide ▴
Rule
BRCA2 PP3 requires BayesDel no-AF ≥0.30 in a clinically important domain and/or SpliceAI ≥0.2.
Evidence considered
- SpliceAI max delta 0.01
- BayesDel no-AF -0.443818
- REVEL 0.182
- residue 1586 lies outside aa 10-40 and aa 2481-3186 domains
Sources
BA1 The population frequency is far below the BA1 threshold. In gnomAD v4.1 the allele frequency is 6.20e-07, which is well below the BRCA2 BA1 threshold of 0.001. Details ▾Hide ▴
Rule
BA1 requires FAF >0.001 in the ENIGMA BRCA2 framework.
Evidence considered
- gnomAD v4.1 total AF 6.195948097781974e-07
Sources
BS1 The population frequency is far below the BS1 threshold. This variant is absent from gnomAD v2.1 and is present in gnomAD v4.1 at 6.20e-07, which is below the BRCA2 BS1_Supporting threshold of 0.00002 and the BS1 threshold of 0.0001. Details ▾Hide ▴
Rule
BS1 requires FAF above ENIGMA BRCA2 benign frequency thresholds.
Evidence considered
- gnomAD v2.1 absent
- gnomAD v4.1 total AF 6.195948097781974e-07
Sources
Not assessed · 10 · no assessment recorded
PS1 No reviewed evidence was identified showing that another nucleotide change causing the same amino acid substitution has already been classified as pathogenic or likely pathogenic under the BRCA2 ENIGMA framework. Details ▾Hide ▴
Rule
PS1 requires a previously classified pathogenic or likely pathogenic variant with the same protein or splicing consequence.
Evidence considered
- no PS1 comparator evidence in the reviewed case materials
Still missing
- A dedicated same-amino-acid comparator review would be needed for PS1.
Sources
PS3 No variant-specific damaging functional study for p.(Thr1586Ile) was identified in the reviewed BRCA2 ENIGMA functional resources, so PS3 cannot be applied. Details ▾Hide ▴
Rule
PS3 requires well-established damaging functional evidence.
Evidence considered
- no exact match in ENIGMA Table 9
- no exact match in HUMU-40-1557 supplementary data
- OncoKB did not identify variant-specific reviewed functional evidence
Still missing
- No exact-match calibrated functional assay result for c.4757C>T / p.(Thr1586Ile) was identified.
Sources
PS4 No case-control or multifactorial likelihood evidence showing enrichment of this variant in affected individuals was identified, so PS4 cannot be applied. Details ▾Hide ▴
Rule
PS4 requires significantly increased prevalence in affected individuals versus controls.
Evidence considered
- no exact match in ST7 reference-set table
- no exact match in HUMU-40-1557 supplementary data
- ClinVar has a single likely benign submission only
Still missing
- No exact-match case-control result or pathogenic-direction multifactorial likelihood ratio was identified.
Sources
PM3 No evidence was identified that this variant has been observed in trans with a pathogenic BRCA2 variant in an individual with BRCA2-related Fanconi anemia, so PM3 cannot be applied. Details ▾Hide ▴
PP1 No segregation likelihood ratio or family segregation dataset was identified for this variant, so PP1 cannot be applied. Details ▾Hide ▴
PP4 No variant-specific clinical-history likelihood ratio was identified for this variant in the reviewed BRCA2 ENIGMA clinical-history resource, so PP4 cannot be applied. Details ▾Hide ▴
Rule
PP4 requires a pathogenic-direction multifactorial clinical likelihood ratio meeting ENIGMA thresholds.
Evidence considered
- no exact-match row for c.4757C>T in the BRCA2 clinical-history LR workbook
Still missing
- No exact c.4757C>T entry was identified in the BRCA2 clinical-history LR table.
Sources
BS2 No qualifying observation of this variant in individuals without Fanconi anemia features was identified under the BRCA2 point-based BS2 framework, so BS2 cannot be applied. Details ▾Hide ▴
Rule
BS2 in BRCA2 requires point-based evidence from observations without recessive disease features.
Evidence considered
- no BS2-supporting observations in reviewed materials
Still missing
- No BS2 point-generating observations were identified.
Sources
BS3 No variant-specific functional study showing normal or near-normal BRCA2 function was identified in the reviewed ENIGMA functional resources, so BS3 cannot be applied. Details ▾Hide ▴
Rule
BS3 requires well-established functional evidence showing no damaging effect.
Evidence considered
- no exact match in ENIGMA Table 9
- no exact match in HUMU-40-1557 supplementary data
- OncoKB did not identify variant-specific reviewed functional evidence
Still missing
- No exact-match calibrated benign functional assay result for c.4757C>T / p.(Thr1586Ile) was identified.
Sources
BS4 No quantitative non-segregation evidence was identified for this variant, so BS4 cannot be applied. Details ▾Hide ▴
Rule
BS4 requires quantitative lack-of-segregation evidence meeting ENIGMA thresholds.
Evidence considered
- no exact-match non-segregation evidence in reviewed materials
Still missing
- No lack-of-segregation likelihood ratio was identified.
Sources
BP5 No variant-specific benign-direction clinical-history likelihood ratio was identified for this variant in the reviewed BRCA2 ENIGMA clinical-history resource, so BP5 cannot be applied. Details ▾Hide ▴
Rule
BP5 requires a benign-direction multifactorial clinical likelihood ratio meeting ENIGMA thresholds.
Evidence considered
- no exact-match row for c.4757C>T in the BRCA2 clinical-history LR workbook
Still missing
- No exact c.4757C>T entry was identified in the BRCA2 clinical-history LR table.
Sources
Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴
PS2 VCEPDe novo evidence is not used for BRCA2 in this framework. Details ▾Hide ▴
PM1 VCEPPM1 is not used for BRCA2 in this ENIGMA framework. Details ▾Hide ▴
PM4 VCEPPM4 is not used for BRCA2 in this ENIGMA framework. Details ▾Hide ▴
PM5 N/AFor BRCA2, PM5 is repurposed for truncating or protein-termination-codon logic rather than classic same-residue missense comparison, and this variant is missense. Details ▾Hide ▴
Rule
BRCA2 ENIGMA uses PM5 for PTC logic, not classic missense same-residue comparison.
Evidence considered
- PM5 candidate review marked classic same-residue PM5 ineligible
- variant is missense
- not truncating
Sources
PM6 VCEPAssumed de novo evidence is not used for BRCA2 in this framework. Details ▾Hide ▴
PP2 VCEPPP2 is not used for BRCA2 in this ENIGMA framework. Details ▾Hide ▴
PP5 VCEPPP5 is not used in this framework. Details ▾Hide ▴
BP2 VCEPBP2 is not used for BRCA2 in this ENIGMA framework. Details ▾Hide ▴
BP3 VCEPBP3 is not used for BRCA2 in this ENIGMA framework. Details ▾Hide ▴
BP4 N/ABP4 is reserved in this framework for variants within clinically important domains that lack predicted impact. Because p.(Thr1586Ile) is outside those domains, benign computational evidence is captured by BP1_Strong rather than BP4. Details ▾Hide ▴
Rule
BRCA2 BP4 applies only within clinically important domains when computational evidence is benign.
Evidence considered
- variant lies outside ENIGMA BRCA2 clinically important domains
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
BP6 VCEPBP6 is not used in this framework. Details ▾Hide ▴
BP7 N/ABP7 is not applicable because this is a missense variant rather than a synonymous or qualifying intronic variant. Details ▾Hide ▴
Rule
BRCA2 BP7 is for RNA-based benign evidence in synonymous or qualifying intronic settings, with limited missense use only for specific RNA assay scenarios.
Evidence considered
- variant consequence is missense p.(Thr1586Ile)
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
Identifiers
- Gene
- BRCA2
- Transcript
- NM_000059.4
- Coding (HGVS c.)
- NM_000059.4:c.4757C>T
- Protein (HGVS p.)
- NP_000050.3:p.(Thr1586Ile)
- GRCh38
- chr13:32339112 C>T
- GRCh37
- chr13:32913249 C>T
- ClinVar
- 3825379
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 / 1,613,958 alleles
AF 6.2e-07 · 0 homozygotes
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 6.2e-07 · 1 / 1,613,958 alleles · 0 hom
| European (non-Finnish)1 / 1,179,920 | 8.5e-07 |
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= 6.19595e-07; MAF= 0.00006%, 1/1613958 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47515e-07; MAF= 0.00008%, 1/1179920 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.182
- BayesDel
- -0.444
How the predictions were used
PP3 Computational evidence does not support a damaging effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, BayesDel no-AF is -0.443818, and p.(Thr1586Ile) lies outside the BRCA2 clinically important domains used for missense PP3 application. Details ▾Hide ▴
Rule
BRCA2 PP3 requires BayesDel no-AF ≥0.30 in a clinically important domain and/or SpliceAI ≥0.2.
Evidence considered
- SpliceAI max delta 0.01
- BayesDel no-AF -0.443818
- REVEL 0.182
- residue 1586 lies outside aa 10-40 and aa 2481-3186 domains
Sources
BP4 N/ABP4 is reserved in this framework for variants within clinically important domains that lack predicted impact. Because p.(Thr1586Ile) is outside those domains, benign computational evidence is captured by BP1_Strong rather than BP4. Details ▾Hide ▴
Rule
BRCA2 BP4 applies only within clinically important domains when computational evidence is benign.
Evidence considered
- variant lies outside ENIGMA BRCA2 clinically important domains
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
BP7 N/ABP7 is not applicable because this is a missense variant rather than a synonymous or qualifying intronic variant. Details ▾Hide ▴
Rule
BRCA2 BP7 is for RNA-based benign evidence in synonymous or qualifying intronic settings, with limited missense use only for specific RNA assay scenarios.
Evidence considered
- variant consequence is missense p.(Thr1586Ile)
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.182. BayesDel score = -0.443818.
1 paper record listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
-
PMID 25394175 ↗A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.Hampel H et al. · 2015No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
1 / 1,613,958 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.010
Open source ↗
ClinVar
1 Likely benign
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/3825379/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/13-32913249-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr13-32339112-C-T?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/13-32339112-C-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000059.4%3Ac.4757…
- OncoKB ↗www.oncokb.org/gene/BRCA2/T1586I
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=BRCA2+c.4757C%3ET
- 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= 6.19595e-07; MAF= 0.00006%, 1/1613958 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47515e-07; MAF= 0.00008%, 1/1179920 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Likely benign (1 clinical laboratory). (ClinVarID = 3825379)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.182. BayesDel score = -0.443818.
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.