About BRCA2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRCA2 c.9257-18C>A, p.?
Classification
Not classified
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. Select a step to read what it means.
Not classified yet.Select a step to read what it means.
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
BP4Supporting
BP4 · supporting
This intronic variant is outside the native donor and acceptor splice sites and SpliceAI predicts no significant splice impact, with a maximum delta score of 0.01, which is below the BRCA2 BP4 threshold of 0.1. This supports a benign computational interpretation.
Recorded classification: Not classified
No source classification-combination explanation was recorded.
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
10 / 1,607,522 alleles
gnomAD v4.1: 10 / 1,607,522 alleles. Recorded AF 6.22075e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.24689e-05; MAF= 0.00125%, 3/240598 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.78686e-05; MAF= 0.00279%, 3/107648 alleles, homozygotes = 0); grpmax FAF= 7.41e-06.
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.
ClinVar submissions
5 reported laboratory submissions
3 Likely benign · 1 Benign · 1 Uncertain significance.
Context only
ClinVar ↗
No screenshot for this evidence
Functional evidence
Statement recorded
In progress — evidence not uploaded yet.
No listed criterion applied
OncoKB ↗
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Context only
COSMIC ↗
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 · 8 not assessed · 13 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.9257-18C>A variant has been reported in ClinVar, where most clinical laboratory submissions classify it as likely benign or benign, although one submission remains uncertain.
This variant is present at very low frequency in population databases, with 3/240598 alleles in gnomAD v2.1 and 10/1607522 alleles in gnomAD v4.1; these frequencies are below the BS1 and BA1 thresholds but do not meet the PM2 absence requirement.
In a published RNA study, RT-PCR showed no aberrant splicing for this variant, and the BRCA multifactorial splicing dataset also records no aberration, which is consistent with no measurable splice disruption.
Computational splicing prediction supports a benign interpretation, with SpliceAI showing a maximum delta score of 0.01, below the BRCA2 BP4 threshold of 0.1 and well below the PP3 threshold of 0.2.
No criteria match.
Met · 1
BP4 SupportingThis intronic variant is outside the native donor and acceptor splice sites and SpliceAI predicts no significant splice impact, with a maximum delta score of 0.01, which is below the BRCA2 BP4 threshold of 0.1. This supports a benign computational interpretation. Details ▾Hide ▴
Rule
BRCA2 ENIGMA BP4 for intronic variants outside ±1,2 with SpliceAI ≤0.1.
Evidence considered
- Variant position c.9257-18 is not at ±1
- 2.
- SpliceAI max delta score 0.01.
Sources
Not met · 6 · evaluated, threshold not reached
PVS1 This intronic variant is at c.9257-18, outside the canonical ±1,2 splice consensus positions used for BRCA2 PVS1 null-variant application, and SpliceAI does not predict a splice-disrupting effect (max delta score 0.01). Available evidence does not support a loss-of-function mechanism for this variant. Details ▾Hide ▴
Rule
BRCA2 ENIGMA PVS1 requires a null variant category or damaging mRNA evidence.
Evidence considered
- BRCA2 VCEP PVS1 rule applies to canonical splice/null variants or damaging RNA evidence.
- Variant-level PVS1 scaffold classifies this variant outside default null-variant buckets.
- SpliceAI max delta score 0.01.
Sources
PM2 This variant is not absent from population databases. It is present in gnomAD v2.1 at 3/240598 alleles (AF 0.00125%) and in gnomAD v4.1 at 10/1607522 alleles (AF 0.00062%), so the BRCA2 PM2 absence requirement is not met. Details ▾Hide ▴
Rule
BRCA2 ENIGMA PM2 requires absence from gnomAD in adequately covered regions.
Evidence considered
- gnomAD v2.1: 3/240598 alleles.
- gnomAD v4.1: 10/1607522 alleles.
Sources
PP3 Computational evidence does not support a splice-altering effect. SpliceAI shows a maximum delta score of 0.01, which is below the BRCA2 PP3 threshold of 0.2. Details ▾Hide ▴
Rule
BRCA2 ENIGMA PP3 for splicing requires SpliceAI ≥0.2.
Evidence considered
- SpliceAI DS_DL 0.01
- all other delta scores 0.00.
Sources
BA1 Population frequency is well below the BRCA2 BA1 threshold. The highest observed filter allele frequency is 7.41e-06 in gnomAD v2.1 and 3.68e-06 in gnomAD v4.1, both below the BA1 threshold of 0.001. Details ▾Hide ▴
Rule
BRCA2 ENIGMA BA1 requires FAF >0.001.
Evidence considered
- gnomAD v2.1 grpmax FAF 7.41e-06.
- gnomAD v4.1 grpmax FAF 3.68e-06.
Sources
BS1 Population frequency is below the BRCA2 BS1 threshold. The highest observed filter allele frequency is 7.41e-06 in gnomAD v2.1 and 3.68e-06 in gnomAD v4.1, both below the supporting threshold of 0.00002. Details ▾Hide ▴
Rule
BRCA2 ENIGMA BS1 requires FAF >0.00002 for supporting or >0.0001 for strong benign evidence.
Evidence considered
- gnomAD v2.1 grpmax FAF 7.41e-06.
- gnomAD v4.1 grpmax FAF 3.68e-06.
Sources
BP7 A published RT-PCR study reported no aberrant splicing for this variant, and the multifactorial splicing dataset also lists no aberration; however, the variant is at c.9257-18, which is not in the intronic position range automatically eligible for BP7 from BP4 alone under the BRCA2 rule, and no explicit ENIGMA BP7 RNA calibration assignment was retrieved for this exact variant. BP7 is therefore not applied at this stage. Details ▾Hide ▴
Rule
BRCA2 ENIGMA BP7 requires either eligible intronic position with BP4 or calibrated RNA evidence.
Evidence considered
- SpliceAI max delta score 0.01.
- HUMU SuppT1 lists 'No aberration' and RT-PCR with PMID 16619214 for c.9257-18C>A.
Still missing
- An explicit ENIGMA-calibrated BP7 RNA assignment for this exact variant was not retrieved.
Sources
Not assessed · 8 · no assessment recorded
PS1 No published comparator variant with the same proven splicing effect was identified to support PS1 for this intronic BRCA2 variant. Details ▾Hide ▴
Rule
BRCA2 ENIGMA PS1 splicing comparator rule.
Evidence considered
- BRCA2 ENIGMA allows PS1 for variants with the same predicted or demonstrated splicing impact as a previously classified pathogenic or likely pathogenic variant.
Still missing
- A validated pathogenic or likely pathogenic comparator with the same demonstrated splicing consequence was not identified.
Sources
PS4 No case-control study showing significant enrichment of this variant in affected individuals compared with controls was identified. Details ▾Hide ▴
Rule
BRCA2 ENIGMA PS4 requires significant case-control enrichment.
Evidence considered
- ClinVar submissions do not establish the BRCA2 PS4 case-control requirement.
Still missing
- A variant-specific case-control analysis meeting the BRCA2 PS4 odds ratio and p-value thresholds was not identified.
Sources
PM3 No evidence was identified that this variant was observed in trans with a pathogenic BRCA2 variant in an individual with BRCA2-related Fanconi anemia features. Details ▾Hide ▴
Rule
BRCA2 ENIGMA PM3 recessive-disease rule.
Evidence considered
- BRCA2 ENIGMA PM3 is restricted to BRCA2-related Fanconi anemia contexts.
Still missing
- No qualifying recessive-disease proband and phase data were identified.
Sources
PP1 No quantitative segregation data were identified for this variant. Details ▾Hide ▴
Rule
BRCA2 ENIGMA PP1 segregation rule.
Evidence considered
- BRCA2 ENIGMA PP1 requires quantitative segregation likelihood ratios.
Still missing
- No family-based likelihood ratio for segregation was identified.
Sources
PP4 No qualifying BRCA2 clinical-history likelihood ratio from the ENIGMA-approved LR resource was identified for this variant. Details ▾Hide ▴
Rule
BRCA2 ENIGMA PP4 uses calibrated multifactorial clinical likelihood ratios only.
Evidence considered
- BRCA2 clinical-history LR workbook did not yield an exact row for this variant.
Still missing
- No exact variant match was found in the BRCA2 clinical-history LR table.
Sources
BS2 No data were identified showing this variant in a context that would score BS2 under the BRCA2 Fanconi anemia framework. Details ▾Hide ▴
Rule
BRCA2 ENIGMA BS2 recessive-disease rule.
Evidence considered
- BRCA2 ENIGMA BS2 uses a point-based recessive-disease framework.
Still missing
- No qualifying adult observations or point-based BRCA2 BS2 evidence were identified.
Sources
BS4 No quantitative non-segregation data were identified for this variant. Details ▾Hide ▴
Rule
BRCA2 ENIGMA BS4 non-segregation rule.
Evidence considered
- BRCA2 ENIGMA BS4 requires quantitative segregation likelihood ratios.
Still missing
- No family-based likelihood ratio against pathogenicity was identified.
Sources
BP5 No qualifying BRCA2 clinical-history likelihood ratio against pathogenicity was identified for this variant in the ENIGMA-approved LR resource. Details ▾Hide ▴
Rule
BRCA2 ENIGMA BP5 uses calibrated multifactorial clinical likelihood ratios only.
Evidence considered
- BRCA2 clinical-history LR workbook did not yield an exact row for this variant.
Still missing
- No exact variant match was found in the BRCA2 clinical-history LR table.
Sources
Not applicable · 13· recorded as not applicable Show reasons ▾Hide reasons ▴
PS2 VCEPDe novo occurrence is not a criterion used in this BRCA2 VCEP framework. Details ▾Hide ▴
VCEP rule
Criterion not applicable in BRCA2 ENIGMA VCEP.
Evidence considered
- PS2 is listed as not applicable in the BRCA2 specification.
Sources
PS3 N/AFor BRCA2 intronic variants, RNA-only evidence is interpreted under PVS1 or BP7 rather than PS3. No protein-based functional study supporting a damaging effect was identified for this variant. Details ▾Hide ▴
Rule
BRCA2 ENIGMA PS3 excludes RNA-only damaging evidence from direct PS3 use.
Evidence considered
- BRCA2 ENIGMA routes mRNA-only damaging evidence to PVS1 rather than PS3.
Sources
PM1 VCEPPM1 is not used as an independent criterion in this BRCA2 VCEP framework and is captured within the bioinformatic/domain rules for PP3 and BP4. Details ▾Hide ▴
VCEP rule
Criterion not applicable in BRCA2 ENIGMA VCEP.
Evidence considered
- PM1 is listed as not applicable in the BRCA2 specification.
Sources
PM4 VCEPPM4 is not applicable for this BRCA2 VCEP framework. Details ▾Hide ▴
VCEP rule
Criterion not applicable in BRCA2 ENIGMA VCEP.
Evidence considered
- PM4 is listed as not applicable in the BRCA2 specification.
Sources
PM5 N/AIn this BRCA2 VCEP, PM5 is repurposed for protein-truncating variant logic rather than classic same-residue missense comparison, and this intronic non-truncating variant does not fall in that PM5 category. Details ▾Hide ▴
Rule
BRCA2 ENIGMA PM5_PTC rule only.
Evidence considered
- PM5 candidate harvest marked classic same-residue PM5 as ineligible.
- Variant is not a protein-truncating variant.
Sources
cspec ↗pm5_candidates
PM6 VCEPPM6 is not a criterion used in this BRCA2 VCEP framework. Details ▾Hide ▴
VCEP rule
Criterion not applicable in BRCA2 ENIGMA VCEP.
Evidence considered
- PM6 is listed as not applicable in the BRCA2 specification.
Sources
PP2 VCEPPP2 is not a criterion used in this BRCA2 VCEP framework. Details ▾Hide ▴
VCEP rule
Criterion not applicable in BRCA2 ENIGMA VCEP.
Evidence considered
- PP2 is listed as not applicable in the BRCA2 specification.
Sources
PP5 VCEPPP5 is not used in this VCEP framework. Details ▾Hide ▴
VCEP rule
Criterion not applicable in BRCA2 ENIGMA VCEP.
Evidence considered
- PP5 is explicitly not for use in the BRCA2 specification.
Sources
BS3 N/AFor this intronic variant, RNA-only evidence is interpreted under BP7 rather than BS3. No protein-based functional study showing no damaging effect was identified. Details ▾Hide ▴
Rule
BRCA2 ENIGMA BS3 excludes RNA-only benign evidence from direct BS3 use.
Evidence considered
- BRCA2 ENIGMA routes mRNA-only benign evidence to BP7 rather than BS3.
Sources
BP1 N/ABP1 in this BRCA2 VCEP applies to silent, missense, or in-frame variants outside key domains with no splice impact, and does not apply to an intronic variant. Details ▾Hide ▴
Rule
BRCA2 ENIGMA BP1 variant-type restriction.
Evidence considered
- BP1 rule scope excludes intronic variants.
Sources
BP2 VCEPBP2 is not a criterion used in this BRCA2 VCEP framework. Details ▾Hide ▴
VCEP rule
Criterion not applicable in BRCA2 ENIGMA VCEP.
Evidence considered
- BP2 is listed as not applicable in the BRCA2 specification.
Sources
BP3 VCEPBP3 is not applicable in this BRCA2 VCEP framework. Details ▾Hide ▴
VCEP rule
Criterion not applicable in BRCA2 ENIGMA VCEP.
Evidence considered
- BP3 is listed as not applicable in the BRCA2 specification.
Sources
BP6 VCEPBP6 is not a criterion used in this BRCA2 VCEP framework. Details ▾Hide ▴
VCEP rule
Criterion not applicable in BRCA2 ENIGMA VCEP.
Evidence considered
- BP6 is listed as not applicable in the BRCA2 specification.
Sources
Identifiers
- Gene
- BRCA2
- Transcript
- NM_000059.4
- Coding (HGVS c.)
- NM_000059.4:c.9257-18C>A
- Protein (HGVS p.)
- NP_000050.3:p.?
- GRCh38
- chr13:32394671 C>A
- GRCh37
- chr13:32968808 C>A
- ClinVar
- 52791
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
10 / 1,607,522 alleles
AF 6.22e-06 · 0 homozygotes · FAF 3.68e-06
gnomAD v2.1
3 / 240,598 alleles
AF 1.25e-05 · 0 homozygotes · FAF 7.41e-06
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 6.2e-06 · 10 / 1,607,522 alleles · 0 hom · FAF 3.7e-06
| South Asian2 / 90,348 | 2.2e-05 |
| European (non-Finnish)8 / 1,175,998 | 6.8e-06 |
0 alternate alleles recorded in 8 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 1.2e-05 · 3 / 240,598 alleles · 0 hom · FAF 7.4e-06
| European (non-Finnish)3 / 107,648 | 2.8e-05 |
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= 6.22075e-06; MAF= 0.00062%, 10/1607522 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 2.21366e-05; MAF= 0.00221%, 2/90348 alleles, homozygotes = 0); grpmax FAF= 3.68e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.24689e-05; MAF= 0.00125%, 3/240598 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.78686e-05; MAF= 0.00279%, 3/107648 alleles, homozygotes = 0); grpmax FAF= 7.41e-06.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP4 SupportingThis intronic variant is outside the native donor and acceptor splice sites and SpliceAI predicts no significant splice impact, with a maximum delta score of 0.01, which is below the BRCA2 BP4 threshold of 0.1. This supports a benign computational interpretation. Details ▾Hide ▴
Rule
BRCA2 ENIGMA BP4 for intronic variants outside ±1,2 with SpliceAI ≤0.1.
Evidence considered
- Variant position c.9257-18 is not at ±1
- 2.
- SpliceAI max delta score 0.01.
Sources
PP3 Computational evidence does not support a splice-altering effect. SpliceAI shows a maximum delta score of 0.01, which is below the BRCA2 PP3 threshold of 0.2. Details ▾Hide ▴
Rule
BRCA2 ENIGMA PP3 for splicing requires SpliceAI ≥0.2.
Evidence considered
- SpliceAI DS_DL 0.01
- all other delta scores 0.00.
Sources
BP7 A published RT-PCR study reported no aberrant splicing for this variant, and the multifactorial splicing dataset also lists no aberration; however, the variant is at c.9257-18, which is not in the intronic position range automatically eligible for BP7 from BP4 alone under the BRCA2 rule, and no explicit ENIGMA BP7 RNA calibration assignment was retrieved for this exact variant. BP7 is therefore not applied at this stage. Details ▾Hide ▴
Rule
BRCA2 ENIGMA BP7 requires either eligible intronic position with BP4 or calibrated RNA evidence.
Evidence considered
- SpliceAI max delta score 0.01.
- HUMU SuppT1 lists 'No aberration' and RT-PCR with PMID 16619214 for c.9257-18C>A.
Still missing
- An explicit ENIGMA-calibrated BP7 RNA assignment for this exact variant was not retrieved.
Sources
Statement
In silico
In progress — evidence not uploaded yet.
9 paper records 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 16619214 ↗Intronic alterations in BRCA1 and BRCA2: effect on mRNA splicing fidelity and expression.Chen X et al. · 2006No paper-specific finding is recorded.
-
PMID 21523855 ↗Comprehensive prediction of mRNA splicing effects of BRCA1 and BRCA2 variants.Mucaki EJ et al. · 2011No paper-specific finding is recorded.
-
PMID 23918944 ↗Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers.No paper-specific finding is recorded.
-
PMID 25382762 ↗Functional classification of BRCA2 DNA variants by splicing assays in a large minigene with 9 exons.Acedo A et al. · 2015No paper-specific finding is recorded.
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PMID 25741868 ↗Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.No paper-specific finding is recorded.
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PMID 10923033 ↗The breast cancer information core: database design, structure, and scope.Szabo C et al. · 2000No paper-specific finding is recorded.
-
PMID 12692171 ↗American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility.American Society of Clinical Oncology · 2003No paper-specific finding is recorded.
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PMID 15604628 ↗Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.Trepanier A et al. · 2004No paper-specific finding is recorded.
-
PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
10 / 1,607,522 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
3 Likely benign · 1 Benign · 1 Uncertain significance
Open source ↗
COSMIC
Captured COSMIC 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/52791/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/13-32968808-C-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr13-32394671-C-A?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/13-32394671-C-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000059.4%3Ac.9257…
- OncoKB ↗www.oncokb.org/gene/BRCA2/?
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=BRCA2+c.9257-18C%3EA
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= 6.22075e-06; MAF= 0.00062%, 10/1607522 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 2.21366e-05; MAF= 0.00221%, 2/90348 alleles, homozygotes = 0); grpmax FAF= 3.68e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.24689e-05; MAF= 0.00125%, 3/240598 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.78686e-05; MAF= 0.00279%, 3/107648 alleles, homozygotes = 0); grpmax FAF= 7.41e-06.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
In progress — evidence not uploaded yet.
In silico
In progress — evidence not uploaded yet.
Functional
In progress — evidence not uploaded yet.
Somatic
In progress — evidence not uploaded yet.
Literature
In progress — evidence not uploaded yet.