About BRCA2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRCA2 c.1924_1925insGG, p.(Ser642TrpfsTer3)
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: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PVS1Very strong
PVS1 · very strong
This variant is a frameshift change, NM_000059.4:c.1924_1925insGG, predicted to cause p.(Ser642TrpfsTer3) [p.(S642Wfs*3)] with truncation very early in BRCA2. The ENIGMA BRCA2 specification recognizes loss of function as an established disease mechanism, and the exon-level Table 4 assigns exon 11 truncating variants full PVS1 weight; available SpliceAI data do not suggest an alternative splice-driven explanation (max delta score 0.01).
PM5Strong
PM5 · strong
This variant is a protein-truncating variant in BRCA2 exon 11. In the ENIGMA BRCA2 specification, PM5 is repurposed for truncating variants, and Table 4 shows that exon 11 is eligible for PM5_Strong (PTC), meaning a different proven pathogenic truncating variant has been established in this exon and additional pathogenic weight is allowed for another exon 11 truncating variant.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Pathogenic
ENIGMA BRCA1/BRCA2 Specification v1.2 Table 3 final-classification framework (CSPEC/VCEP 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.
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
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
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.
28 criteria with recorded statuses: 2 met · 7 not met · 10 not assessed · 9 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.1924_1925insGG (p.(Ser642TrpfsTer3), p.(S642Wfs*3)) variant has not been observed in somatic cancers in COSMIC and has not been reported in ClinVar.
This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population databases.
This early frameshift predicts premature truncation of BRCA2, and the ENIGMA BRCA2 specification supports full PVS1 weight with additional PM5_Strong (PTC) applicability for truncating variants in exon 11.
SpliceAI predicts no significant splice impact for this variant (max delta score 0.01), which is below the ENIGMA PP3 splice threshold of 0.2 and supports a truncating rather than splice-altering mechanism.
No criteria match.
Met · 2
PVS1 Very strongThis variant is a frameshift change, NM_000059.4:c.1924_1925insGG, predicted to cause p.(Ser642TrpfsTer3) [p.(S642Wfs*3)] with truncation very early in BRCA2. The ENIGMA BRCA2 specification recognizes loss of function as an established disease mechanism, and the exon-level Table 4 assigns exon 11 truncating variants full PVS1 weight; available SpliceAI data do not suggest an alternative splice-driven explanation (max delta score 0.01). Details ▾Hide ▴
Rule
ENIGMA BRCA2 PVS1 for null variants using Table 4 exon-specific weighting.
Evidence considered
- Frameshift consequence p.(Ser642TrpfsTer3) / p.(S642Wfs*3)
- BRCA2 loss of function established in ENIGMA framework
- BRCA2 exon 11 Table 4 designation: PVS1
- SpliceAI max delta 0.01
Sources
PM5 StrongThis variant is a protein-truncating variant in BRCA2 exon 11. In the ENIGMA BRCA2 specification, PM5 is repurposed for truncating variants, and Table 4 shows that exon 11 is eligible for PM5_Strong (PTC), meaning a different proven pathogenic truncating variant has been established in this exon and additional pathogenic weight is allowed for another exon 11 truncating variant. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PM5 for PTC variants uses exon-specific Table 4 weighting; exon 11 is PM5_Strong (PTC).
Evidence considered
- PM5 mode is PTC gene-specific rather than classic same-residue PM5
- BRCA2 exon 11 listed as PM5_Strong (PTC) applicable in Table 4
Sources
Not met · 7 · evaluated, threshold not reached
PS1 Available evidence does not show that this variant has the same amino acid change or the same established splice effect as a previously classified pathogenic or likely pathogenic comparator. This is a truncating frameshift variant, so the BRCA2 PS1 rules were not satisfied. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PS1 requires the same protein change or same established splice effect as a previously classified comparator.
Evidence considered
- Frameshift consequence rather than same-amino-acid substitution
- No established matched splice comparator identified
Sources
PP3 Available computational evidence does not support PP3 under the BRCA2 ENIGMA rules. SpliceAI predicts no significant splice impact with a max delta score of 0.01, which is below the PP3 splice threshold of 0.2, and this frameshift variant is not a missense or in-frame change within a domain eligible for BayesDel-based PP3 use. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PP3 applies to eligible missense/in-frame variants with BayesDel support or to eligible variants with SpliceAI >=0.2.
Evidence considered
- SpliceAI max delta 0.01
- REVEL and BayesDel not applicable because this is not an SNV
- Variant type is frameshift rather than missense/in-frame
Sources
BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore is far below the BRCA2 ENIGMA BA1 threshold of filter allele frequency greater than 0.1%. BA1 is not met. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BA1 requires filter allele frequency >0.1% in a non-founder population.
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 and therefore does not exceed the BRCA2 ENIGMA BS1 thresholds of filter allele frequency above 0.002% or 0.01%. BS1 is not met. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BS1 requires filter allele frequency above the specified threshold in a non-founder population.
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
Sources
BP1 This variant is not a silent, missense, or in-frame change outside a clinically important functional domain. It is a truncating frameshift variant, so BP1 is not met. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BP1_Strong applies only to eligible non-truncating variants outside defined functional domains with no splice effect predicted.
Evidence considered
- Variant type is frameshift
- BP1 rule is restricted to silent/missense/in-frame variants
Sources
BP4 Available computational evidence does not support BP4 for this variant under the BRCA2 ENIGMA rules. Although SpliceAI predicts no significant splice impact with a max delta score of 0.01, BP4 is restricted to eligible missense, in-frame, silent, or intronic variants, and this allele is a truncating frameshift variant. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BP4 applies only to eligible non-truncating variant classes with no predicted splice or protein impact.
Evidence considered
- SpliceAI max delta 0.01
- Variant type is frameshift and not BP4-eligible
Sources
BP7 This variant is not a silent or intronic change, and no RNA-only benign splicing evidence specific to this allele was identified. BP7 is not met. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BP7 is limited to eligible silent, intronic, or certain RNA-only contexts.
Evidence considered
- Variant type is frameshift
- SpliceAI max delta 0.01 does not by itself satisfy BP7 for this variant class
Sources
Not assessed · 10 · no assessment recorded
PS3 No variant-specific calibrated functional study result for NM_000059.4:c.1924_1925insGG was identified in the ENIGMA BRCA2 functional-assay table. Curated literature resources point to BRCA2 loss-of-function biology in general, but the available evidence does not provide a criterion-ready PS3 assignment for this exact allele. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PS3 requires well-established variant-specific damaging functional evidence.
Evidence considered
- No exact match found in ENIGMA Table 9
- OncoKB linked general BRCA2 functional literature
Still missing
- No exact variant entry was identified in the ENIGMA Table 9 functional dataset.
- No direct variant-specific calibrated protein assay result was confirmed for this allele.
Sources
PS4 No case-control evidence or quantified excess of this variant in affected individuals versus controls was identified. Available evidence is insufficient to show a statistically significant increase in prevalence required for PS4. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PS4 requires significant enrichment in affected individuals compared with controls.
Evidence considered
- No ClinVar record found
- No COSMIC record found
- No PS4-supporting local BRCA2 observation table entry identified
Still missing
- No exact variant case-control dataset was identified.
- No odds ratio or p-value was available for this allele.
Sources
PM2 This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is consistent with rarity in population databases. However, the BRCA2 ENIGMA PM2 rule requires absence in the specified non-cancer datasets with adequate local read depth, and the available evidence reviewed here did not document the required coverage threshold. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PM2_Supporting requires absence from specified gnomAD control datasets with adequate coverage.
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
Still missing
- Average read depth of at least 25 around the variant was not documented in the reviewed population evidence.
- The ENIGMA rule cites gnomAD v3.1 non-cancer in addition to v2.1
- that exact dataset confirmation was not directly available here.
Sources
PM3 No evidence was identified that this variant has been observed in trans with another pathogenic BRCA2 variant in an individual with a phenotype consistent with BRCA2-related Fanconi anemia. Available evidence does not support PM3 at this time. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PM3 requires in-trans observations with BRCA2-related Fanconi anemia evidence.
Evidence considered
- No in-trans observation identified
- No Fanconi anemia phenotype data identified
Still missing
- No confirmed biallelic case was identified.
- No phasing data or Fanconi anemia phenotype data were available for this allele.
Sources
PP1 No segregation data were identified for this variant. Available evidence does not show co-segregation with disease in affected family members, so PP1 cannot be applied. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PP1 requires quantitative co-segregation evidence.
Evidence considered
- No family segregation evidence identified
Still missing
- No quantitative segregation likelihood ratio was available.
- No informative pedigree data were identified for this allele.
Sources
PP4 No variant-specific multifactorial clinical-history likelihood ratio meeting BRCA2 ENIGMA thresholds was identified. Available evidence is insufficient to apply PP4. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PP4 requires a qualifying multifactorial clinical likelihood ratio toward pathogenicity.
Evidence considered
- No exact variant clinical-history LR identified
Still missing
- No exact match for this variant was confirmed in the BRCA2 clinical-history LR workbook.
- No qualifying LR value of at least 2.08 was available.
Sources
BS2 No evidence was identified showing this variant in individuals without features of BRCA2-related Fanconi anemia in a way that would satisfy the ENIGMA point-based BS2 rule. Available evidence is insufficient to apply BS2. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BS2 requires qualifying observations in the absence of recessive disease features.
Evidence considered
- No BS2 qualifying observations identified
Still missing
- No point-based qualifying proband data were available.
- No phenotype-reviewed adult carrier evidence was identified for this allele.
Sources
BS3 No variant-specific calibrated benign functional study result for NM_000059.4:c.1924_1925insGG was identified in the ENIGMA BRCA2 functional-assay table. Available evidence does not support BS3. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BS3 requires well-established variant-specific functional evidence showing no damaging effect.
Evidence considered
- No exact match found in ENIGMA Table 9
Still missing
- No exact variant entry was identified in the ENIGMA Table 9 functional dataset.
- No direct variant-specific calibrated assay showing no damaging effect was confirmed.
Sources
vcep_specifications_table9_v1_2_2024_11_18oncokb ↗
BS4 No lack-of-segregation data were identified for this variant. Available evidence does not provide the quantitative non-segregation likelihood ratio required for BS4. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BS4 requires quantitative lack-of-segregation evidence.
Evidence considered
- No quantitative non-segregation evidence identified
Still missing
- No informative family non-segregation data were identified.
- No BS4 likelihood ratio at or below the ENIGMA threshold was available.
Sources
BP5 No variant-specific multifactorial clinical-history likelihood ratio in the benign direction was identified for this allele. Available evidence is insufficient to apply BP5. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BP5 requires a qualifying multifactorial clinical likelihood ratio against pathogenicity.
Evidence considered
- No exact variant clinical-history LR identified
Still missing
- No exact match for this variant was confirmed in the BRCA2 clinical-history LR workbook.
- No qualifying LR value at or below 0.48 was available.
Sources
Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴
PS2 VCEPThis criterion is not applicable in the BRCA2 ENIGMA specification for this review context. Details ▾Hide ▴
VCEP rule
Not applicable per ENIGMA BRCA2 specification.
Evidence considered
- Criterion marked not applicable in BRCA2 CSPEC
Sources
PM1 VCEPThis criterion is not applicable in the BRCA2 ENIGMA specification for this review context. Details ▾Hide ▴
VCEP rule
Not applicable per ENIGMA BRCA2 specification.
Evidence considered
- Criterion marked not applicable in BRCA2 CSPEC
Sources
PM4 VCEPThis criterion is not applicable in the BRCA2 ENIGMA specification for this review context. Details ▾Hide ▴
VCEP rule
Not applicable per ENIGMA BRCA2 specification.
Evidence considered
- Criterion marked not applicable in BRCA2 CSPEC
Sources
PM6 VCEPThis criterion is not applicable in the BRCA2 ENIGMA specification for this review context. Details ▾Hide ▴
VCEP rule
Not applicable per ENIGMA BRCA2 specification.
Evidence considered
- Criterion marked not applicable in BRCA2 CSPEC
Sources
PP2 VCEPThis criterion is not applicable in the BRCA2 ENIGMA specification for this review context. Details ▾Hide ▴
VCEP rule
Not applicable per ENIGMA BRCA2 specification.
Evidence considered
- Criterion marked not applicable in BRCA2 CSPEC
Sources
PP5 VCEPThis criterion is not applicable in the BRCA2 ENIGMA specification for this review context. Details ▾Hide ▴
VCEP rule
Not applicable per ENIGMA BRCA2 specification.
Evidence considered
- Criterion marked not applicable in BRCA2 CSPEC
Sources
BP2 VCEPThis criterion is not applicable in the BRCA2 ENIGMA specification for this review context. Details ▾Hide ▴
VCEP rule
Not applicable per ENIGMA BRCA2 specification.
Evidence considered
- Criterion marked not applicable in BRCA2 CSPEC
Sources
BP3 VCEPThis criterion is not applicable in the BRCA2 ENIGMA specification for this review context. Details ▾Hide ▴
VCEP rule
Not applicable per ENIGMA BRCA2 specification.
Evidence considered
- Criterion marked not applicable in BRCA2 CSPEC
Sources
BP6 VCEPThis criterion is not applicable in the BRCA2 ENIGMA specification for this review context. Details ▾Hide ▴
VCEP rule
Not applicable per ENIGMA BRCA2 specification.
Evidence considered
- Criterion marked not applicable in BRCA2 CSPEC
Sources
Identifiers
- Gene
- BRCA2
- Transcript
- NM_000059.4
- Coding (HGVS c.)
- NM_000059.4:c.1924_1925insGG
- Protein (HGVS p.)
- NP_000050.3:p.(Ser642TrpfsTer3)
- GRCh38
- chr13:32336279 T>TGG
- GRCh37
- chr13:32910416 T>TGG
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
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
- Not available
How the predictions were used
PP3 Available computational evidence does not support PP3 under the BRCA2 ENIGMA rules. SpliceAI predicts no significant splice impact with a max delta score of 0.01, which is below the PP3 splice threshold of 0.2, and this frameshift variant is not a missense or in-frame change within a domain eligible for BayesDel-based PP3 use. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PP3 applies to eligible missense/in-frame variants with BayesDel support or to eligible variants with SpliceAI >=0.2.
Evidence considered
- SpliceAI max delta 0.01
- REVEL and BayesDel not applicable because this is not an SNV
- Variant type is frameshift rather than missense/in-frame
Sources
BP4 Available computational evidence does not support BP4 for this variant under the BRCA2 ENIGMA rules. Although SpliceAI predicts no significant splice impact with a max delta score of 0.01, BP4 is restricted to eligible missense, in-frame, silent, or intronic variants, and this allele is a truncating frameshift variant. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BP4 applies only to eligible non-truncating variant classes with no predicted splice or protein impact.
Evidence considered
- SpliceAI max delta 0.01
- Variant type is frameshift and not BP4-eligible
Sources
BP7 This variant is not a silent or intronic change, and no RNA-only benign splicing evidence specific to this allele was identified. BP7 is not met. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BP7 is limited to eligible silent, intronic, or certain RNA-only contexts.
Evidence considered
- Variant type is frameshift
- SpliceAI max delta 0.01 does not by itself satisfy BP7 for this variant class
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
5 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 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.
-
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.
-
PMID 24312913 ↗A comprehensive focus on global spectrum of BRCA1 and BRCA2 mutations in breast 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 0.010
Open source ↗
ClinVar
Captured ClinVar source record
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/?term=NM_000059.4%3Ac.1924_1925insGG
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/13-32910416-T-TGG?dataset=gno…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr13-32336279-T-TGG?dataset=…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000059.4%3Ac.1924…
- OncoKB ↗www.oncokb.org/gene/BRCA2/S642Wfs*3
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=BRCA2+c.1924_1925insGG
- 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 is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
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.