About BRCA2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRCA2 c.2818C>T, p.(Gln940Ter)
Classification
Pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.
Pathogenic.A 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: 5
Benign evidence criteria: 0
Pathogenic criteria applied · 5
PVS1Very strong
PVS1 · very strong
This variant is a nonsense change, NM_000059.4:c.2818C>T (p.Gln940Ter), predicted to truncate BRCA2 early in exon 11. Germline loss of function is an established BRCA2 disease mechanism, and the ENIGMA BRCA2 exon-level PVS1 table assigns exon 11 protein-truncating variants to PVS1.
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada, supporting rarity in reference populations. Under the BRCA2 specification, absence from gnomAD supports PM2_Supporting.
PM5Strong
PM5 · strong
In the BRCA2 ENIGMA specification, PM5 is repurposed for protein-truncating variants rather than classic same-residue missense logic. This nonsense variant lies in exon 11, and the ENIGMA exon-level table assigns exon 11 protein-truncating variants to PM5_Strong (PTC).
PP4Supporting
PP4 · supporting
BRCA2 clinical-history likelihood analysis reported a likelihood ratio of 2.54 for c.2818C>T based on 3 probands. This is above the ENIGMA PP4 supporting threshold of 2.08 and below the moderate threshold of 4.3, so PP4_Supporting is met.
PP5Supporting
PP5 · supporting
Expert panel Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) classified as Pathogenic.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Pathogenic
Official ClinGen ENIGMA BRCA1/BRCA2 v1.2 final-classification framework using Table 3 criteria-combination rules.
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
11 reported laboratory submissions
11 Pathogenic.
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
1 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV107497862, n = 1 times).
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 · 4 not met · 6 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.2818C>T (p.Gln940Ter) variant has been observed once in somatic cancer in COSMIC and has been reported in ClinVar as Pathogenic, including ENIGMA expert panel review.
This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada, supporting rarity in reference populations.
This nonsense variant truncates BRCA2 at codon 940 in exon 11, where the ENIGMA BRCA2 specification assigns PVS1 and PM5_Strong (PTC) for protein-truncating variants, consistent with BRCA2 loss of function as an established disease mechanism.
BRCA2 clinical-history likelihood analysis reported a likelihood ratio of 2.54 from 3 probands, meeting the ENIGMA threshold for PP4_Supporting.
SpliceAI predicts no significant splice impact for this variant with a maximum delta score of 0.00, and the BayesDel no-AF score is 0.288, which does not reach the BRCA2 PP3 protein-impact threshold of 0.30.
No criteria match.
Met · 5
PVS1 Very strongThis variant is a nonsense change, NM_000059.4:c.2818C>T (p.Gln940Ter), predicted to truncate BRCA2 early in exon 11. Germline loss of function is an established BRCA2 disease mechanism, and the ENIGMA BRCA2 exon-level PVS1 table assigns exon 11 protein-truncating variants to PVS1. Details ▾Hide ▴
Rule
ENIGMA BRCA2 v1.2 PVS1 for exon 11 protein-truncating variants
Evidence considered
- p.Gln940Ter nonsense variant
- BRCA2 loss of function established as disease mechanism
- ENIGMA Table 4 exon 11 PTC row = PVS1
Sources
cspec ↗vcep_specifications_table4_v1_2_2024_11_18pvs1_gene_contextpvs1_variant_assessmentPMID:25741868 ↗
PM2 SupportingThis variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada, supporting rarity in reference populations. Under the BRCA2 specification, absence from gnomAD supports PM2_Supporting. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PM2_Supporting for absence from gnomAD
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
- Absent from gnomAD-Canada v1.0
Still missing
- Average read depth of at least 25 at this site was not documented in the retrieved population summaries.
Sources
PM5 StrongIn the BRCA2 ENIGMA specification, PM5 is repurposed for protein-truncating variants rather than classic same-residue missense logic. This nonsense variant lies in exon 11, and the ENIGMA exon-level table assigns exon 11 protein-truncating variants to PM5_Strong (PTC). Details ▾Hide ▴
Rule
ENIGMA BRCA2 PM5_Strong (PTC) for exon 11 protein-truncating variants
Evidence considered
- Variant is a PTC/nonsense change
- PM5 mode is PTC gene-specific
- ENIGMA Table 4 exon 11 PTC row = PM5_Strong (PTC)
Sources
PP4 SupportingBRCA2 clinical-history likelihood analysis reported a likelihood ratio of 2.54 for c.2818C>T based on 3 probands. This is above the ENIGMA PP4 supporting threshold of 2.08 and below the moderate threshold of 4.3, so PP4_Supporting is met. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PP4 based on multifactorial clinical-history LR
Evidence considered
- Clinical-history LR = 2.535982693047889
- N probands = 3
- PP4 thresholds: Supporting >=2.08
- Moderate >=4.3
Sources
Not met · 4 · evaluated, threshold not reached
PS4 This variant has been reported in ClinVar and has been observed once in COSMIC, but no case-control study showing significantly increased prevalence in affected individuals with p-value 0.05 or less and odds ratio 4 or greater was identified. These observations do not meet BRCA2 PS4 requirements. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PS4 requires p<=0.05 and OR>=4 with lower confidence interval excluding 2.0
Evidence considered
- ClinVar pathogenic submissions including ENIGMA expert panel review
- COSMIC somatic count = 1
- No qualifying PS4 case-control statistics identified
Still missing
- A qualifying case-control analysis would be needed to support PS4.
Sources
BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the BRCA2 BA1 threshold of filter allele frequency greater than 0.1%. BA1 is not met. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BA1 requires FAF >0.1%
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
Sources
BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, so it does not exceed the BRCA2 BS1 supporting threshold of filter allele frequency greater than 0.002% or strong threshold greater than 0.01%. BS1 is not met. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BS1 requires elevated population frequency
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
Sources
BP5 BRCA2 clinical-history likelihood analysis reported a likelihood ratio of 2.54 for c.2818C>T based on 3 probands. This is above the benign BP5 supporting threshold of 0.48 and is in the pathogenic rather than benign direction, so BP5 is not met. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BP5 based on multifactorial clinical-history LR
Evidence considered
- Clinical-history LR = 2.535982693047889
- BP5 supporting threshold <=0.48
Sources
Not assessed · 6 · no assessment recorded
PS3 No variant-specific calibrated functional assay result for c.2818C>T was identified in the ENIGMA BRCA1/2 functional assay table. General BRCA2 loss-of-function biology does not by itself provide criterion-ready PS3 evidence for this specific variant. Details ▾Hide ▴
Evidence considered
- No c.2818C>T or p.Gln940Ter entry found in ENIGMA Table 9
- OncoKB provides literature leads but not criterion-ready assay assignment
Still missing
- Direct review of any variant-specific functional literature would be needed to support PS3.
Sources
vcep_specifications_table9_v1_2_2024_11_18oncokb ↗PMID:10570174 ↗PMID:11239455 ↗PMID:20878484 ↗PMID:22193408 ↗PMID:24312913 ↗
PM3 No evidence was identified that this variant was observed in trans with another BRCA2 variant in a patient with BRCA2-related Fanconi anemia. PM3 was therefore not assessed. Details ▾Hide ▴
Evidence considered
- No Fanconi anemia-specific co-occurrence data identified
Still missing
- Phenotype and phase data from BRCA2-related Fanconi anemia cases would be needed to assess PM3.
Sources
PP1 No quantitative co-segregation data were identified for this variant, so PP1 could not be assessed. Details ▾Hide ▴
Evidence considered
- No segregation likelihood ratio identified
Still missing
- Family-based likelihood ratio data would be needed to assess PP1.
Sources
BS2 No evidence was identified that this variant was observed in individuals without features of BRCA2-related Fanconi anemia in a manner that could be scored under the BRCA2 BS2 point system. BS2 was not assessed. Details ▾Hide ▴
Evidence considered
- No BS2 point-based evidence identified
Still missing
- Point-based unaffected or phenotype-negative observations would be needed to assess BS2.
Sources
BS3 No variant-specific calibrated functional study showing no damaging effect was identified for c.2818C>T in the ENIGMA BRCA1/2 functional assay table. BS3 was therefore not assessed. Details ▾Hide ▴
Evidence considered
- No c.2818C>T or p.Gln940Ter entry found in ENIGMA Table 9
Still missing
- Direct review of any variant-specific benign functional data would be needed to support BS3.
Sources
vcep_specifications_table9_v1_2_2024_11_18oncokb ↗PMID:10570174 ↗PMID:11239455 ↗PMID:20878484 ↗PMID:22193408 ↗PMID:24312913 ↗
BS4 No quantitative lack-of-segregation data were identified for this variant, so BS4 could not be assessed. Details ▾Hide ▴
Evidence considered
- No BS4 likelihood ratio identified
Still missing
- Family-based likelihood ratio data showing lack of segregation would be needed to assess BS4.
Sources
Not applicable · 13· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/AThis variant is a nonsense change, and no same-amino-acid missense comparator or same-splicing comparator evidence was identified for PS1 under the BRCA2 specification. Details ▾Hide ▴
PS2 VCEPNo de novo framework is used for this BRCA2 VCEP assessment, and no confirmed de novo evidence was identified. Details ▾Hide ▴
PM1 VCEPPM1 is not used in this BRCA2 VCEP framework for this variant context. Details ▾Hide ▴
PM4 VCEPPM4 is not used in this BRCA2 VCEP framework. Details ▾Hide ▴
PM6 VCEPNo de novo framework is used for this BRCA2 VCEP assessment, and no de novo evidence was identified. Details ▾Hide ▴
PP2 VCEPPP2 is not used in this BRCA2 VCEP framework. Details ▾Hide ▴
PP3 N/AThis variant is a nonsense change rather than a missense, in-frame, silent, or non-canonical intronic variant used for BRCA2 PP3. SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, and the BayesDel no-AF score is 0.288, below the BRCA2 PP3 protein-impact threshold of 0.30. Details ▾Hide ▴
Evidence considered
- Variant consequence is nonsense
- SpliceAI max delta score = 0.00
- BayesDel no-AF = 0.288255
Sources
BP1 N/AThis variant is a nonsense change, not a silent, missense, or in-frame variant outside a clinically important domain, so BP1 does not apply. Details ▾Hide ▴
BP2 VCEPBP2 is not used in this BRCA2 VCEP framework. Details ▾Hide ▴
BP3 VCEPBP3 is not used in this BRCA2 VCEP framework. Details ▾Hide ▴
BP4 N/AThis variant is a nonsense change rather than a missense, in-frame, silent, or non-canonical intronic variant used for BRCA2 BP4. SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, but the BP4 rule is not designed for this exonic stop-gain context. Details ▾Hide ▴
Evidence considered
- Variant consequence is nonsense
- SpliceAI max delta score = 0.00
- BayesDel no-AF = 0.288255
Sources
BP6 VCEPBP6 is not used in this BRCA2 VCEP framework. Details ▾Hide ▴
BP7 N/AThis variant is a nonsense change, not a silent or qualifying intronic variant for BP7. SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, but BP7 is not used for this protein-truncating context. Details ▾Hide ▴
Evidence considered
- Variant consequence is nonsense
- SpliceAI max delta score = 0.00
Sources
Identifiers
- Gene
- BRCA2
- Transcript
- NM_000059.4
- Coding (HGVS c.)
- NM_000059.4:c.2818C>T
- Protein (HGVS p.)
- NP_000050.3:p.(Gln940Ter)
- GRCh38
- chr13:32337173 C>T
- GRCh37
- chr13:32911310 C>T
- ClinVar
- 37804
- COSMIC
- COSV107497862
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
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
- 0.288
How the predictions were used
PP3 N/AThis variant is a nonsense change rather than a missense, in-frame, silent, or non-canonical intronic variant used for BRCA2 PP3. SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, and the BayesDel no-AF score is 0.288, below the BRCA2 PP3 protein-impact threshold of 0.30. Details ▾Hide ▴
Evidence considered
- Variant consequence is nonsense
- SpliceAI max delta score = 0.00
- BayesDel no-AF = 0.288255
Sources
BP4 N/AThis variant is a nonsense change rather than a missense, in-frame, silent, or non-canonical intronic variant used for BRCA2 BP4. SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, but the BP4 rule is not designed for this exonic stop-gain context. Details ▾Hide ▴
Evidence considered
- Variant consequence is nonsense
- SpliceAI max delta score = 0.00
- BayesDel no-AF = 0.288255
Sources
BP7 N/AThis variant is a nonsense change, not a silent or qualifying intronic variant for BP7. SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, but BP7 is not used for this protein-truncating context. Details ▾Hide ▴
Evidence considered
- Variant consequence is nonsense
- SpliceAI max delta score = 0.00
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = 0.288255.
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
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PMID 10570174 ↗Truncated BRCA2 is cytoplasmic: implications for cancer-linked mutations.No paper-specific finding is recorded.
-
PMID 11239455 ↗BRCA2 is required for homology-directed repair of chromosomal breaks.No paper-specific finding is recorded.
-
PMID 20878484 ↗A new mutation of BRCA2 gene in an Italian healthy woman with familial breast cancer history.No paper-specific finding is recorded.
-
PMID 22193408 ↗BRCA1 and BRCA2: different roles in a common pathway of genome protection.No paper-specific finding is recorded.
-
PMID 24312913 ↗A comprehensive focus on global spectrum of BRCA1 and BRCA2 mutations in breast cancer.No paper-specific finding is recorded.
-
PMID 20104584 ↗Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study.Borg A et al. · 2010No paper-specific finding is recorded.
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PMID 23918944 ↗Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers.No paper-specific finding is recorded.
-
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.
-
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
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
11 Pathogenic
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/37804/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/13-32911310-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr13-32337173-C-T?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/13-32337173-C-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000059.4%3Ac.2818…
- OncoKB ↗www.oncokb.org/gene/BRCA2/Q940*
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=140330079
- 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
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 (11 clinical laboratories) and as Pathogenic by Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) (expert panel). (ClinVarID = 37804)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = 0.288255.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV107497862, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.