About BRCA2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRCA2 c.9117+2T>C, p.?
Classification
Likely pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.
Likely pathogenic.A likely pathogenic 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: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PVS1Very strong
PVS1 · very strong
NM_000059.3:c.9117+2T>C is a canonical +2 splice donor variant in BRCA2 exon 23, which encodes residues within the DNA binding domain (aa 2985-3039). Loss of function is an established disease mechanism for BRCA2 hereditary breast and ovarian cancer. ENIGMA Specification Table 4 assigns PVS1 (RNA) to this variant, indicating that RNA assay data confirm aberrant splicing leading to a null allele. The exon is within a clinically important functional domain and PVS1 is applied at full (very strong) weight per the ENIGMA PVS1 decision framework.
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 (non-cancer, exome subset) and gnomAD v4.1 (non-cancer) outbred populations, meeting the ENIGMA PM2_Supporting threshold (absent from controls in outbred populations). Under the ENIGMA specification, PM2 is only applicable at Supporting strength; the default ACMG Moderate strength is not used.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Likely pathogenic
ENIGMA BRCA1/BRCA2 VCEP Specification v1.2.0, Table 3 combination rules applied to adjudicated criteria. One Very Strong criterion (PVS1) plus one Supporting criterion (PM2) satisfies the Likely Pathogenic threshold under Table 3: [1 Very Strong + 1 Supporting -> Likely Pathogenic]. ENIGMA point system yields 8 + 1 = 9 points, within the Likely Pathogenic range (6-9). No benign criteria are met, so no conflicting evidence.
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
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
1 reported laboratory submissions
1 Pathogenic.
Context only
ClinVar ↗
No screenshot for this evidence
Functional evidence
Not recorded
No standalone functional evidence summary is recorded in evidence_summary.functional.
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.
29 criteria with recorded statuses: 2 met · 10 not met · 2 not assessed · 15 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_000059.3:c.9117+2T>C is a canonical +2 splice donor variant in BRCA2 exon 23, disrupting the GT dinucleotide of the donor splice site. ENIGMA Specification Table 4 assigns PVS1 (RNA) at very strong weight based on confirmed aberrant splicing by RNA assay. The exon encodes residues 2985-3039 within the DNA binding domain, a clinically important functional region where loss of function is an established disease mechanism for hereditary breast and ovarian cancer.
The variant is absent from gnomAD v2.1 and v4.1 outbred populations, meeting ENIGMA PM2_Supporting (absent from controls). No filter allele frequency data suggest the variant is present in any population database.
No formal case-control study (PS4), co-segregation analysis (PP1), or clinical-history likelihood ratio (PP4/BP5) meeting ENIGMA quantitative thresholds is available. The variant is not listed in the Li et al. 2020 BRCA2 clinical-history LR table (PMID:31853058). ENIGMA PS3, BS3, BS1, BS2, BS4, and BA1 criteria are not met, and BP1, BP4, BP7, PM1, PM5, PP2, PP5, BP2, BP6 are not applicable under the ENIGMA specification.
Under ENIGMA Table 3 combining rules, one Very Strong criterion (PVS1) and one Supporting criterion (PM2) is sufficient for a Likely Pathogenic classification.
No criteria match.
Met · 2
PVS1 Very strongNM_000059.3:c.9117+2T>C is a canonical +2 splice donor variant in BRCA2 exon 23, which encodes residues within the DNA binding domain (aa 2985-3039). Loss of function is an established disease mechanism for BRCA2 hereditary breast and ovarian cancer. ENIGMA Specification Table 4 assigns PVS1 (RNA) to this variant, indicating that RNA assay data confirm aberrant splicing leading to a null allele. The exon is within a clinically important functional domain and PVS1 is applied at full (very strong) weight per the ENIGMA PVS1 decision framework. Details ▾Hide ▴
Evidence considered
- Canonical +2 splice donor variant at exon 23 intron boundary
- disrupting the GT dinucleotide
- ENIGMA Table 4 assigns PVS1 (RNA) — RNA assay data confirm aberrant splicing
- BRCA2 exon 23 encodes DNA binding domain (aa 2985-3039)
- a clinically important functional domain
- Loss of function is a well-established disease mechanism for BRCA2
Sources
PM2 SupportingThis variant is absent from gnomAD v2.1 (non-cancer, exome subset) and gnomAD v4.1 (non-cancer) outbred populations, meeting the ENIGMA PM2_Supporting threshold (absent from controls in outbred populations). Under the ENIGMA specification, PM2 is only applicable at Supporting strength; the default ACMG Moderate strength is not used. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (0 alleles observed)
- Absent from gnomAD v4.1 (0 alleles observed)
Sources
Not met · 10 · evaluated, threshold not reached
PS4 ENIGMA PS4 requires a formal case-control study with p≤0.05 and odds ratio ≥4 (lower CI excludes 2.0). No such study was identified. The variant has been submitted to ClinVar as Pathogenic by one clinical laboratory (ClinVar ID 267714, single submitter, criteria provided), but this does not satisfy the ENIGMA PS4 case-control threshold. The exploratory search identified evidence of multiple clinical submitters reporting the variant in probands, but no peer-reviewed case-control study with OR and confidence intervals is available. Details ▾Hide ▴
Evidence considered
- ClinVar classification: Pathogenic
- criteria provided
- single submitter (VariationID 267714)
- No formal case-control study with OR ≥4 identified
Still missing
- A published case-control study with OR and confidence intervals would be needed to meet PS4
Sources
PP1 No formal quantitative co-segregation analysis with likelihood ratio meeting ENIGMA thresholds (LR ≥2.08 for Supporting) was identified. Exploratory search found indirect indications of familial segregation in ClinVar and BIC database annotations, but no peer-reviewed pedigree analysis or computed LOD score is available. Details ▾Hide ▴
Evidence considered
- No formal segregation LR or LOD score available
Still missing
- A published co-segregation analysis with LR ≥2.08 would be needed to apply PP1
PP3 Under ENIGMA rules, PP3 for predicted splicing (SpliceAI ≥0.2) is applicable for silent, missense, in-frame, and intronic variants outside donor/acceptor ±1,2 positions. This variant is at the canonical +2 donor position and PVS1 has already been applied for the splice disruption mechanism. Per ENIGMA guidance, PP3 is not double-counted when PVS1 captures the same splice-effect evidence. Additionally, SpliceAI returned a max delta score of 0.00, which does not meet the PP3 threshold for splice prediction. Details ▾Hide ▴
Evidence considered
- Canonical +2 splice donor variant
- PVS1 already captures splice disruption
- SpliceAI max delta score = 0.00 (below PP3 threshold of ≥0.2)
Sources
PP4 No ENIGMA PP4 clinical-history likelihood ratio is available. The variant (c.9117+2T>C) was not found in the Li et al. 2020 (PMID:31853058) BRCA2 clinical-history LR table. No other multifactorial likelihood data supporting pathogenicity via phenotype specificity was identified. Details ▾Hide ▴
Evidence considered
- Variant not listed in Li et al. 2020 BRCA2 clinical-history LR table
Still missing
- Multifactorial clinical data with LR ≥2.08 would be needed to apply PP4
Sources
vcep_pmid_31853058_brca2_clinical_history_lr
BA1 Variant is absent from gnomAD v2.1 and v4.1. ENIGMA BA1 requires filter allele frequency (FAF) >0.1% (FAF > 0.001) in gnomAD non-founder populations. The variant does not meet this threshold. Details ▾Hide ▴
BS1 Variant is absent from gnomAD v2.1 and v4.1. ENIGMA BS1_Strong requires FAF >0.01% (FAF > 0.0001) in gnomAD non-founder populations. The variant does not meet this threshold. Details ▾Hide ▴
BS2 No evidence of observation in healthy adults without features of Fanconi anemia phenotype was identified. ENIGMA BS2 requires co-observation with a pathogenic variant in the same gene in the absence of recessive disease features, with points assigned per proband. No such data are available. Details ▾Hide ▴
Still missing
- Observation in healthy adults with a co-occurring BRCA2 pathogenic variant would be needed
BS3 No well-established in vitro or in vivo functional studies showing no damaging effect on protein function were identified. The variant is not listed in ENIGMA Specification Table 9. The available splicing evidence instead demonstrates a damaging effect, supporting PVS1 (RNA). Details ▾Hide ▴
Evidence considered
- Variant not present in ENIGMA Table 9 functional assay results
Sources
vcep_specifications_table9_v1_2_2024_11_18
BS4 No evidence of lack of segregation in affected family members (non-segregation) was identified. ENIGMA BS4 requires quantitative co-segregation analysis with LR ≤0.48 for Supporting weight. No such data are available. Details ▾Hide ▴
Still missing
- Non-segregation data with LR ≤0.48 would be needed to apply BS4
BP5 No ENIGMA BP5 clinical-history likelihood ratio supporting benignity is available. The variant (c.9117+2T>C) was not found in the Li et al. 2020 (PMID:31853058) BRCA2 clinical-history LR table. No other multifactorial likelihood data supporting benignity was identified. Details ▾Hide ▴
Evidence considered
- Variant not listed in Li et al. 2020 BRCA2 clinical-history LR table
Still missing
- Multifactorial clinical data with LR ≤0.48 would be needed to apply BP5
Sources
vcep_pmid_31853058_brca2_clinical_history_lr
Not assessed · 2 · no assessment recorded
PS1 No comparator splice variant at the same position with a confirmed (likely) pathogenic classification was identified in the case materials. ENIGMA PS1 rules for splicing variants require a previously classified (likely) pathogenic variant with the same predicted splicing impact; no such comparator was evaluated. Details ▾Hide ▴
Still missing
- A systematic search for comparators at the c.9117+2 position (e.g.
- c.9117+2T>G
- c.9117+2T>A) may identify a previously classified variant with the same predicted splice impact.
PS3 Under the ENIGMA framework, well-established functional studies measuring effect on mRNA transcript profile are applied as PVS1 (RNA), not PS3. PS3 is reserved for protein-level functional assays. This variant is not listed in ENIGMA Specification Table 9 (curated protein-level functional assay results). The mRNA splicing evidence is captured under PVS1 (RNA). Details ▾Hide ▴
Evidence considered
- ENIGMA redirects mRNA splicing functional evidence to PVS1 (RNA)
- Variant not present in Table 9 functional assay dataset
Sources
cspec ↗vcep_specifications_table9_v1_2_2024_11_18
Not applicable · 15· recorded as not applicable Show reasons ▾Hide reasons ▴
PS2 VCEPDe novo criterion not applicable — no de novo testing data for this variant was provided or identified. Details ▾Hide ▴
No further detail was recorded.
PM1 VCEPPM1 is not applicable under the ENIGMA BRCA2 VCEP specification. The criterion is considered a component of bioinformatic analysis captured by PP3/BP4 rather than applied independently. Details ▾Hide ▴
Sources
PM3 N/ASkipped per case directive — trivially not applicable. Details ▾Hide ▴
No further detail was recorded.
PM4 VCEPSkipped per case directive — trivially not applicable. Details ▾Hide ▴
No further detail was recorded.
PM5 N/AUnder ENIGMA, PM5 is repurposed as PM5_PTC for protein termination codon (nonsense/frameshift) variants annotated as PVS1 in exons where a different proven pathogenic PTC variant has been observed. NM_000059.3:c.9117+2T>C is a canonical splice donor variant, not a direct PTC variant (nonsense/frameshift). Although it is predicted to produce a PTC via aberrant splicing and has PVS1 (RNA) weight per Table 4, PM5_PTC is reserved for variants that are themselves PTCs. Classic same-residue PM5 also does not apply as this is not a missense variant. Details ▾Hide ▴
Evidence considered
- BRCA2 exon 23 is not in PM5_N/A exons and has PM5_Strong (PTC) assignment for PTC variants
- c.9117+2T>C is a canonical splice variant
- not a direct nonsense or frameshift variant
Sources
PM6 VCEPPM6 is not applicable under the ENIGMA BRCA2 VCEP specification. Details ▾Hide ▴
Sources
PP2 VCEPPP2 is not applicable under the ENIGMA BRCA2 VCEP specification. Details ▾Hide ▴
Sources
PP5 VCEPPP5 is not applicable under the ENIGMA BRCA2 VCEP specification (criterion not for use as recommended by the ClinGen SVI VCEP Review Committee). Details ▾Hide ▴
Sources
BP1 N/ABP1 applies to missense, silent, or in-frame variants outside clinically important functional domains with no splicing predicted. NM_000059.3:c.9117+2T>C is a canonical splice donor variant at the +2 position; BP1 is not applicable to splice site variants. Details ▾Hide ▴
Sources
BP2 VCEPBP2 is not applicable under the ENIGMA BRCA2 VCEP specification. Details ▾Hide ▴
Sources
BP3 VCEPBP3 is not applicable — the variant is not an in-frame deletion/insertion in a repetitive region without known function. Details ▾Hide ▴
No further detail was recorded.
BP4 N/AENIGMA BP4 applies to intronic variants outside native donor and acceptor splice sites (±1,2 positions) with no predicted splicing impact. This variant is at the canonical +2 donor position, within the native splice site, and ENIGMA Table 4 confirms aberrant splicing via RNA assay data (PVS1 (RNA)). BP4 is not applicable. Details ▾Hide ▴
Evidence considered
- Variant is at canonical +2 donor position
- not outside native splice site
- ENIGMA Table 4 confirms splicing impact via RNA assay (PVS1 (RNA))
Sources
cspec ↗vcep_specifications_table4_v1_2_2024_11_18
BP6 VCEPBP6 is not applicable under the ENIGMA BRCA2 VCEP specification. Details ▾Hide ▴
Sources
BP7 N/AENIGMA BP7 (RNA) applies to intronic and silent variants where RNA assay shows no splicing impact. This variant has confirmed splicing impact per ENIGMA Table 4 (assigned PVS1 (RNA)), demonstrating aberrant splicing. BP7 is not applicable. Details ▾Hide ▴
Evidence considered
- ENIGMA Table 4 assigns PVS1 (RNA) — RNA assay confirms splicing defect
- contradicting BP7
Sources
cspec ↗vcep_specifications_table4_v1_2_2024_11_18
PS5 N/APS5 is not applicable — this is a splice variant, not a missense variant at a residue where a different pathogenic missense has been reported. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- BRCA2
- Transcript
- NM_000059.3
- Coding (HGVS c.)
- NM_000059.3:c.9117+2T>C
- Protein (HGVS p.)
- NP_000050.2:p.?
- GRCh38
- chr13:32379915 T>C
- GRCh37
- chr13:32954052 T>C
- ClinVar
- 267714
Gene diagram
Every interpreted variant in BRCA2, mapped onto the exon structure of NM_000059.3. Select a row to find it on the plot.
BRCA2NM_000059.3
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
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- 0.321
How the predictions were used
PP3 Under ENIGMA rules, PP3 for predicted splicing (SpliceAI ≥0.2) is applicable for silent, missense, in-frame, and intronic variants outside donor/acceptor ±1,2 positions. This variant is at the canonical +2 donor position and PVS1 has already been applied for the splice disruption mechanism. Per ENIGMA guidance, PP3 is not double-counted when PVS1 captures the same splice-effect evidence. Additionally, SpliceAI returned a max delta score of 0.00, which does not meet the PP3 threshold for splice prediction. Details ▾Hide ▴
Evidence considered
- Canonical +2 splice donor variant
- PVS1 already captures splice disruption
- SpliceAI max delta score = 0.00 (below PP3 threshold of ≥0.2)
Sources
BP4 N/AENIGMA BP4 applies to intronic variants outside native donor and acceptor splice sites (±1,2 positions) with no predicted splicing impact. This variant is at the canonical +2 donor position, within the native splice site, and ENIGMA Table 4 confirms aberrant splicing via RNA assay data (PVS1 (RNA)). BP4 is not applicable. Details ▾Hide ▴
Evidence considered
- Variant is at canonical +2 donor position
- not outside native splice site
- ENIGMA Table 4 confirms splicing impact via RNA assay (PVS1 (RNA))
Sources
cspec ↗vcep_specifications_table4_v1_2_2024_11_18
BP7 N/AENIGMA BP7 (RNA) applies to intronic and silent variants where RNA assay shows no splicing impact. This variant has confirmed splicing impact per ENIGMA Table 4 (assigned PVS1 (RNA)), demonstrating aberrant splicing. BP7 is not applicable. Details ▾Hide ▴
Evidence considered
- ENIGMA Table 4 assigns PVS1 (RNA) — RNA assay confirms splicing defect
- contradicting BP7
Sources
cspec ↗vcep_specifications_table4_v1_2_2024_11_18
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = 0.321175.
8 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
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PMID 23918944 ↗Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers.Phillips KA et al. · 2013No paper-specific finding is recorded.
-
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 17392385 ↗American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography.Saslow D et al. · 2007American Cancer Society guideline on breast MRI screening as an adjunct to mammography. Discusses BRCA1/BRCA2 mutation carriers at the gene level for screening recommendations. No specific BRCA2 variant is evaluated.Does not name this variant
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PMID 17508274 ↗Risk assessment and genetic counseling for hereditary breast and ovarian cancer: recommendations of the National Society of Genetic Counselors.Berliner JL et al. · 2007No paper-specific finding is recorded.
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PMID 19305347 ↗ACOG Practice Bulletin No. 103: Hereditary breast and ovarian cancer syndrome.2009ACOG Practice Bulletin on hereditary breast and ovarian cancer syndrome. Reviews clinical management guidelines for BRCA1/BRCA2 mutation carriers at the gene level. No specific BRCA2 variant is evaluated.Does not name this variant
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PMID 20065170 ↗American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility.Robson ME et al. · 2010No paper-specific finding is recorded.
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PMID 20301425 ↗BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer.Adam MP et al. · 1993No paper-specific finding is recorded.
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PMID 23188549 ↗NSGC practice guideline: risk assessment and genetic counseling for hereditary breast and ovarian cancer.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
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
1 Pathogenic
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/267714/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/13-32954052-T-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr13-32379915-T-C?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/13-32379915-T-C
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000059.3%3Ac.9117…
- OncoKB ↗www.oncokb.org/gene/BRCA2/?
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=BRCA2+c.9117+2T%3EC
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
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 Pathogenic (1 clinical laboratory). (ClinVarID = 267714)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = 0.321175.
Somatic
This variant has not previously been reported in somatic cancers (COSMIC).