About BRCA2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRCA2 c.5344C>T, p.(Gln1782Ter)
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: 4
Benign evidence criteria: 0
Pathogenic criteria applied · 4
PVS1Very strong
PVS1 · very strong
NM_000059.4:c.5344C>T is a nonsense variant (p.Gln1782Ter / p.Q1782*) in BRCA2 exon 11, creating a premature termination codon. Loss of function is the established disease mechanism for BRCA2. ENIGMA BRCA1/BRCA2 Specification v1.2 Table 4 assigns PVS1 (Very Strong) to PTC variants in exon 11. The variant is on MANE Select transcript NM_000059.4.
PM2Supporting
PM2 · supporting
NM_000059.4:c.5344C>T is absent from gnomAD v2.1 (non-cancer, exome only subset) and gnomAD v3.1 (non-cancer). Per ENIGMA PM2 rule, absence from both outbred population databases in a region with adequate read depth qualifies for PM2_Supporting.
PM5Strong
PM5 · strong
NM_000059.4:c.5344C>T is a protein termination codon (PTC) variant in BRCA2 exon 11. ENIGMA Table 4 assigns PM5_Strong (PTC) to PTC variants in exon 11, where other proven pathogenic PTC variants have been observed. The PM5_PTC code applies additive weight to PVS1-eligible truncating variants in this exon.
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
ENIGMA BRCA1/BRCA2 Specification v1.2.0 Table 3 point system: PVS1 (Very Strong = 8 points) + PM5_Strong/PTC (Strong = 4 points) + PM2_Supporting (Supporting = 1 point) + PP5_Supporting (Supporting = 1 point) = 14 points, meeting the Pathogenic threshold (>= 10 points). Also satisfies ENIGMA Table 3 all_of Pathogenic rule: 1 Very Strong + 1 Strong (PVS1 + PM5_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
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
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
9 reported laboratory submissions
9 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
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.
26 criteria with recorded statuses: 4 met · 3 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
NM_000059.4:c.5344C>T (p.Gln1782Ter) is a nonsense variant in BRCA2 exon 11, creating a premature termination codon at position 1782 of 3418 amino acids. ENIGMA BRCA1/BRCA2 Specification v1.2 Table 4 assigns PVS1 (Very Strong) to PTC variants in exon 11.
ENIGMA Table 4 assigns PM5_Strong (PTC) to PTC variants in BRCA2 exon 11, where other proven pathogenic PTC variants have been established.
The variant is absent from gnomAD v2.1 and v4.1 population databases, meeting ENIGMA PM2_Supporting.
This variant has been classified as Pathogenic by the ENIGMA expert panel in ClinVar (Variation ID 51842), supported by 9 clinical laboratory submissions.
Applying the ENIGMA Table 3 point system: PVS1 (Very Strong = 8 points) + PM5_Strong (PTC) (Strong = 4 points) + PM2_Supporting (Supporting = 1 point) = 13 points, which reaches the Pathogenic threshold (>= 10 points).
No criteria match.
Met · 4
PVS1 Very strongNM_000059.4:c.5344C>T is a nonsense variant (p.Gln1782Ter / p.Q1782*) in BRCA2 exon 11, creating a premature termination codon. Loss of function is the established disease mechanism for BRCA2. ENIGMA BRCA1/BRCA2 Specification v1.2 Table 4 assigns PVS1 (Very Strong) to PTC variants in exon 11. The variant is on MANE Select transcript NM_000059.4. Details ▾Hide ▴
PM2 SupportingNM_000059.4:c.5344C>T is absent from gnomAD v2.1 (non-cancer, exome only subset) and gnomAD v3.1 (non-cancer). Per ENIGMA PM2 rule, absence from both outbred population databases in a region with adequate read depth qualifies for PM2_Supporting. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (0 alleles in exomes)
- Absent from gnomAD v4.1 (0 alleles in exomes/genomes)
Sources
PM5 StrongNM_000059.4:c.5344C>T is a protein termination codon (PTC) variant in BRCA2 exon 11. ENIGMA Table 4 assigns PM5_Strong (PTC) to PTC variants in exon 11, where other proven pathogenic PTC variants have been observed. The PM5_PTC code applies additive weight to PVS1-eligible truncating variants in this exon. Details ▾Hide ▴
Evidence considered
- ENIGMA Table 4: PM5_Strong (PTC) assigned to PTC variants in BRCA2 exon 11
Sources
vcep_specifications_table4_v1_2_2024_11_18cspec ↗
Not met · 3 · evaluated, threshold not reached
PS4 ENIGMA PS4 requires a case-control study with p-value <= 0.05 and odds ratio >= 4 (lower confidence interval excludes 2.0). No published case-control study meeting these thresholds was identified for NM_000059.4:c.5344C>T. The variant is absent from gnomAD population databases, precluding case-control comparison. Details ▾Hide ▴
Evidence considered
- Variant absent from gnomAD v2.1 and v4.1
- no case-control study identified
Still missing
- No case-control study with sufficient statistical power for this variant
Sources
BA1 ENIGMA BA1 requires filter allele frequency (FAF) above 0.1% (FAF > 0.001) in gnomAD v2.1 (non-cancer, exome only) and/or v3.1 (non-cancer). NM_000059.4:c.5344C>T is absent from both gnomAD v2.1 and v4.1/v3.1. Details ▾Hide ▴
BS1 ENIGMA BS1 Strong requires FAF > 0.01% (FAF > 0.0001) in gnomAD; BS1_Supporting requires FAF > 0.002% (FAF > 0.00002). NM_000059.4:c.5344C>T is absent from both gnomAD v2.1 and v4.1. Allele frequency does not support BS1 at any strength. Details ▾Hide ▴
Not assessed · 6 · no assessment recorded
PS3 ENIGMA Table 9 (curated functional assay results) covers missense and synonymous variants only. NM_000059.4:c.5344C>T is a nonsense variant and is not listed in Table 9. No calibrated functional assay result is available for this variant under the ENIGMA PS3 framework. The functional consequence of protein truncation is addressed by PVS1. Details ▾Hide ▴
Evidence considered
- ENIGMA Table 9 does not include this nonsense variant
Still missing
- No calibrated functional assay result for this specific variant in the ENIGMA framework
Sources
vcep_specifications_table9_v1_2_2024_11_18
PP1 ENIGMA PP1 requires quantitative cosegregation analysis with a Bayes score meeting specific LR thresholds (Supporting >= 2.08:1, Moderate >= 4.3:1, Strong >= 18.7:1). No cosegregation LR data was identified for NM_000059.4:c.5344C>T in the available VCEP materials or published literature. Details ▾Hide ▴
Evidence considered
- No cosegregation LR available for this specific variant in ENIGMA source tables
Still missing
- Quantitative cosegregation analysis data not located for this variant
Sources
PP4 ENIGMA PP4 is assessed via clinical-history likelihood ratio from Li et al. 2020 (PMID:31853058). NM_000059.4:c.5344C>T is not listed in the BRCA2 clinical-history LR spreadsheet. The related variant c.5344C>G has LR=0.70 (neutral zone, 0.48-2.08), which does not support PP4 application. No clinical-history LR data is available for c.5344C>T. Details ▾Hide ▴
Evidence considered
- c.5344C>T not found in Li et al. 2020 BRCA2 clinical-history LR table
- Related variant c.5344C>G has LR=0.70 (neutral)
Still missing
- No clinical-history LR data available for c.5344C>T in the Li et al. 2020 dataset
Sources
BS2 ENIGMA BS2 is applied in the absence of Fanconi Anemia features and requires point-based scoring per proband per Specifications Table 8. No proband-level data was available for adjudication of this criterion. Details ▾Hide ▴
Evidence considered
- No proband data with phenotype information available for BS2 scoring
Still missing
- Proband-level phenotype data required for BS2 point assignment
Sources
BS4 ENIGMA BS4 requires quantitative lack-of-segregation analysis with LR thresholds (Supporting <= 0.48:1, Moderate <= 0.23:1, Strong <= 0.05:1). No segregation data was identified for NM_000059.4:c.5344C>T. Details ▾Hide ▴
Evidence considered
- No segregation analysis data available for this variant
Still missing
- Segregation data not available for BS4 assessment
Sources
BP5 ENIGMA BP5 is assessed via clinical-history likelihood ratio (Li et al. 2020, PMID:31853058). NM_000059.4:c.5344C>T is not listed in the BRCA2 clinical-history LR spreadsheet. No data is available to support or refute BP5 for this variant. Details ▾Hide ▴
Evidence considered
- c.5344C>T not found in Li et al. 2020 BRCA2 clinical-history LR table
Still missing
- Clinical-history LR data not available for c.5344C>T
Sources
Not applicable · 13· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 in the ENIGMA framework applies to missense substitutions at the same amino acid position as a known pathogenic variant, or to splicing variants with the same predicted splicing impact. NM_000059.4:c.5344C>T is a nonsense variant creating a stop codon, not a missense or splicing variant. Details ▾Hide ▴
Evidence considered
- ENIGMA PS1 rules are restricted to missense and splice-site variants
Sources
PS2 VCEPPS2 (de novo) is designated as Not Applicable in the ENIGMA BRCA1/BRCA2 CSPEC criteria set. Details ▾Hide ▴
Sources
PM1 VCEPPM1 is designated as Not Applicable in the ENIGMA BRCA1/BRCA2 CSPEC criteria set. Details ▾Hide ▴
Sources
PM6 VCEPPM6 is designated as Not Applicable in the ENIGMA BRCA1/BRCA2 CSPEC criteria set. Details ▾Hide ▴
Sources
PP2 VCEPPP2 is designated as Not Applicable in the ENIGMA BRCA1/BRCA2 CSPEC criteria set. PP2 (missense in a gene with low rate of benign missense variation) is not used for BRCA2. Details ▾Hide ▴
Sources
PP3 N/AENIGMA PP3 applies to missense or in-frame variants inside a clinically important functional domain with BayesDel no-AF score >= 0.30, or to variants with SpliceAI >= 0.2. NM_000059.4:c.5344C>T is a nonsense variant and does not fall under PP3 rules. SpliceAI max delta = 0.00 (no splicing impact predicted). ENIGMA v1.2 specification clarification notes that PP3 should not be stacked when PVS1 is met. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score = 0.00 (no splice impact)
- BayesDel no-AF score = 0.037 (below 0.30 threshold)
- Nonsense variant type not covered by ENIGMA PP3 rules
Sources
BS3 N/AENIGMA Table 9 (BS3 functional assay results) covers missense and synonymous variants only. NM_000059.4:c.5344C>T is a nonsense/truncating variant; BS3 is not applicable for variants that create a premature termination codon. The loss-of-function consequence is captured by PVS1. Details ▾Hide ▴
Evidence considered
- ENIGMA Table 9 does not assess nonsense variants for BS3
Sources
vcep_specifications_table9_v1_2_2024_11_18cspec ↗
BP1 N/AENIGMA BP1 applies to silent substitutions, missense, or in-frame variants outside a clinically important functional domain with no splicing predicted (SpliceAI <= 0.1). NM_000059.4:c.5344C>T is a nonsense/truncating variant. Details ▾Hide ▴
BP2 VCEPBP2 is designated as Not Applicable in the ENIGMA BRCA1/BRCA2 CSPEC criteria set. Details ▾Hide ▴
Sources
BP4 N/AENIGMA BP4 applies to missense or in-frame variants inside a clinically important functional domain with BayesDel no-AF score <= 0.18 and SpliceAI <= 0.1, or silent/intronic variants with no splicing predicted. NM_000059.4:c.5344C>T is a nonsense variant. Details ▾Hide ▴
BP6 VCEPBP6 is designated as Not Applicable in the ENIGMA BRCA1/BRCA2 CSPEC criteria set. Reliance on prior laboratory classification is replaced by the ENIGMA framework. Details ▾Hide ▴
Sources
BP7 N/AENIGMA BP7 applies to silent/intronic variants or variants with mRNA assay evidence showing no damaging effect on transcript profile. NM_000059.4:c.5344C>T is a nonsense variant creating a stop codon, not a silent or intronic change. Details ▾Hide ▴
Evidence considered
- BP7 rules apply to silent/intronic or mRNA-assay-assessed variants only
Sources
PS5 N/APS5 is not included in the ENIGMA BRCA1/BRCA2 CSPEC criteria set and is designated as not applicable under this framework. Details ▾Hide ▴
Sources
Identifiers
- Gene
- BRCA2
- Transcript
- NM_000059.4
- Coding (HGVS c.)
- NM_000059.4:c.5344C>T
- Protein (HGVS p.)
- NP_000050.3:p.(Gln1782Ter)
- GRCh38
- chr13:32339699 C>T
- GRCh37
- chr13:32913836 C>T
- ClinVar
- 51842
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
0 / 0 alleles
AF 0 · 0 homozygotes · FAF 0
By genetic ancestry
gnomAD-Canada
AF 0 · 0 / 0 alleles · 0 hom
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- 0.037
How the predictions were used
PP3 N/AENIGMA PP3 applies to missense or in-frame variants inside a clinically important functional domain with BayesDel no-AF score >= 0.30, or to variants with SpliceAI >= 0.2. NM_000059.4:c.5344C>T is a nonsense variant and does not fall under PP3 rules. SpliceAI max delta = 0.00 (no splicing impact predicted). ENIGMA v1.2 specification clarification notes that PP3 should not be stacked when PVS1 is met. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score = 0.00 (no splice impact)
- BayesDel no-AF score = 0.037 (below 0.30 threshold)
- Nonsense variant type not covered by ENIGMA PP3 rules
Sources
BP4 N/AENIGMA BP4 applies to missense or in-frame variants inside a clinically important functional domain with BayesDel no-AF score <= 0.18 and SpliceAI <= 0.1, or silent/intronic variants with no splicing predicted. NM_000059.4:c.5344C>T is a nonsense variant. Details ▾Hide ▴
BP7 N/AENIGMA BP7 applies to silent/intronic variants or variants with mRNA assay evidence showing no damaging effect on transcript profile. NM_000059.4:c.5344C>T is a nonsense variant creating a stop codon, not a silent or intronic change. Details ▾Hide ▴
Evidence considered
- BP7 rules apply to silent/intronic or mRNA-assay-assessed variants only
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = 0.0368764.
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.
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PMID 11239455 ↗BRCA2 is required for homology-directed repair of chromosomal breaks.No paper-specific finding is recorded.
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PMID 20878484 ↗A new mutation of BRCA2 gene in an Italian healthy woman with familial breast cancer history.No paper-specific finding is recorded.
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PMID 22193408 ↗BRCA1 and BRCA2: different roles in a common pathway of genome protection.No paper-specific finding is recorded.
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PMID 24312913 ↗A comprehensive focus on global spectrum of BRCA1 and BRCA2 mutations in breast cancer.No paper-specific finding is recorded.
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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.
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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 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
9 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/51842/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/13-32913836-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr13-32339699-C-T?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000059.4%3Ac.5344…
- OncoKB ↗www.oncokb.org/gene/BRCA2/Q1782*
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=BRCA2+c.5344C%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
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant has been reported in ClinVar as Pathogenic (9 clinical laboratories) and as Pathogenic by Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) (expert panel). (ClinVarID = 51842)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = 0.0368764.
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 not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.