About BRCA2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRCA2 c.2830A>T, p.(Lys944Ter)
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 nonsense change, NM_000059.4:c.2830A>T (p.Lys944Ter; p.K944*), in BRCA2, a gene in which loss of function is an established disease mechanism. The variant is located in exon 11, which is designated as PVS1-applicable in the ENIGMA BRCA2 specification, and the predicted premature stop is consistent with a loss-of-function effect.
PM5Strong
PM5 · strong
This protein truncating variant occurs in BRCA2 exon 11. In the ENIGMA BRCA2 exon-level Table 4, exon 11 protein termination codon variants are assigned PM5_Strong (PTC), so PM5 is met at strong strength in addition to PVS1.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Pathogenic
ClinGen ENIGMA BRCA1/BRCA2 Specification v1.2.0 final-classification framework using Table 3 criteria-combination rules from final_classification_framework.
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
6 / 1,613,668 alleles
gnomAD v4.1: 6 / 1,613,668 alleles. Recorded AF 3.71824e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.06375e-05; MAF= 0.00106%, 3/282020 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 4.02123e-05; MAF= 0.00402%, 1/24868 alleles, homozygotes = 0).
No listed criterion applied
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
No listed criterion applied
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB classifies this variant as Likely Oncogenic; biological effect: Likely Loss-of-function.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
Not assessed
No COSMIC evidence statement is recorded in this case.
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 · 3 not met · 9 not assessed · 14 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.2830A>T (p.Lys944Ter; p.K944*) variant has been reported in ClinVar as pathogenic by an expert panel and is classified by OncoKB as likely oncogenic with likely loss of function.
This variant is present at very low frequency in gnomAD, with AF 1.06375e-05 (3/282020 alleles) in v2.1 and AF 3.71824e-06 (6/1613668 alleles) in v4.1, which is below ENIGMA BRCA2 BS1 and BA1 thresholds but means PM2 is not met because the variant is not absent from controls.
This nonsense variant occurs in BRCA2 exon 11, a PVS1-eligible exon in the ENIGMA BRCA2 specification, and exon 11 protein termination codon variants are assigned PM5_Strong (PTC), supporting a loss-of-function interpretation.
SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.00.
No criteria match.
Met · 2
PVS1 Very strongThis variant is a nonsense change, NM_000059.4:c.2830A>T (p.Lys944Ter; p.K944*), in BRCA2, a gene in which loss of function is an established disease mechanism. The variant is located in exon 11, which is designated as PVS1-applicable in the ENIGMA BRCA2 specification, and the predicted premature stop is consistent with a loss-of-function effect. Details ▾Hide ▴
Rule
ENIGMA BRCA2 v1.2 PVS1; BRCA2 exon 11 PTC variants are PVS1-applicable
Evidence considered
- Nonsense variant p.(Lys944Ter)/p.(K944*)
- BRCA2 loss of function is an established disease mechanism
- BRCA2 exon 11 is PVS1-applicable in ENIGMA Table 4
Sources
cspec ↗pvs1_gene_contextpvs1_variant_assessmentvcep_s_p_e_c_i_f_i_c_a_t_i_o_n_s___t_a_b_l_e_4___v_1___2___2_0_2_4___1_1___1_8PMID:16760289 ↗PMID:23096105 ↗
PM5 StrongThis protein truncating variant occurs in BRCA2 exon 11. In the ENIGMA BRCA2 exon-level Table 4, exon 11 protein termination codon variants are assigned PM5_Strong (PTC), so PM5 is met at strong strength in addition to PVS1. Details ▾Hide ▴
Rule
ENIGMA BRCA2 v1.2 PM5_PTC; exon 11 = PM5_Strong (PTC)
Evidence considered
- Variant is a protein truncating variant
- BRCA2 exon 11 carries PM5_Strong (PTC) in ENIGMA Table 4
Sources
cspec ↗vcep_s_p_e_c_i_f_i_c_a_t_i_o_n_s___t_a_b_l_e_4___v_1___2___2_0_2_4___1_1___1_8
Not met · 3 · evaluated, threshold not reached
PM2 This variant is not absent from population databases. It is present in gnomAD v2.1 at AF 1.06375e-05 (3/282020 alleles) and in gnomAD v4.1 at AF 3.71824e-06 (6/1613668 alleles), so the ENIGMA BRCA2 requirement for absence from controls is not met. Details ▾Hide ▴
Rule
ENIGMA BRCA2 v1.2 PM2_Supporting requires absence from controls
Evidence considered
- gnomAD v2.1 AF 1.06375e-05 (3/282020)
- gnomAD v4.1 AF 3.71824e-06 (6/1613668)
Sources
BA1 Population frequency does not meet BA1. The highest observed gnomAD v4.1 filter allele frequency is 7.9e-07, which is below the ENIGMA BRCA2 BA1 threshold of 0.001, and the observed allele counts are also very low. Details ▾Hide ▴
Rule
ENIGMA BRCA2 v1.2 BA1 requires FAF >0.001
Evidence considered
- gnomAD v4.1 grpmax FAF 7.9e-07
- gnomAD v2.1 AF 1.06375e-05
Sources
BS1 Population frequency does not meet BS1. The highest observed gnomAD v4.1 filter allele frequency is 7.9e-07, which is below the ENIGMA BRCA2 BS1_Supporting threshold of 0.00002 and far below the BS1 threshold of 0.0001. Details ▾Hide ▴
Rule
ENIGMA BRCA2 v1.2 BS1 thresholds are FAF >0.00002 for Supporting and >0.0001 for Strong
Evidence considered
- gnomAD v4.1 grpmax FAF 7.9e-07
- gnomAD v2.1 AF 1.06375e-05
Sources
Not assessed · 9 · no assessment recorded
PS3 Available evidence supports loss of BRCA2 function for truncating variants in general, but no variant-specific calibrated functional study or ENIGMA Table 9 assignment was identified for this variant. The available data therefore do not support formal PS3 application. Details ▾Hide ▴
Rule
ENIGMA BRCA2 v1.2 PS3 requires well-established functional evidence or a Table 9 code assignment
Evidence considered
- OncoKB classifies the variant as likely oncogenic with likely loss of function
- No matching calibrated PS3 entry was found in ENIGMA Table 9
Still missing
- No variant-specific ENIGMA Table 9 PS3 assignment was identified
Sources
oncokb ↗vcep_s_p_e_c_i_f_i_c_a_t_i_o_n_s___t_a_b_l_e_9___v_1___2___2_0_2_4___1_1___1_8PMID:10570174 ↗PMID:11239455 ↗
PS4 This variant has been reported in affected individuals and is listed in ClinVar as pathogenic, but no case-control study meeting the ENIGMA BRCA2 PS4 requirement of p≤0.05 with OR≥4 and lower confidence interval excluding 2.0 was identified. The available evidence is therefore insufficient for PS4. Details ▾Hide ▴
Rule
ENIGMA BRCA2 v1.2 PS4 requires significant enrichment in affected individuals versus controls
Evidence considered
- ClinVar expert panel pathogenic classification
- Published case observations without qualifying case-control statistics
Still missing
- No qualifying case-control data or quantitative enrichment analysis was identified
Sources
PM3 No evidence was identified that this variant was observed in trans in an individual with BRCA2-related Fanconi anemia. PM3 was therefore not assessed. Details ▾Hide ▴
Rule
ENIGMA BRCA2 v1.2 PM3 is reserved for BRCA2-related Fanconi anemia contexts
Still missing
- No trans observations in BRCA2-related Fanconi anemia were identified
Sources
PP1 No quantitative co-segregation analysis meeting ENIGMA BRCA2 PP1 thresholds was identified. PP1 was therefore not assessed. Details ▾Hide ▴
Rule
ENIGMA BRCA2 v1.2 PP1 requires quantitative segregation evidence
Still missing
- No segregation likelihood ratio meeting PP1 thresholds was identified
Sources
PP4 No multifactorial likelihood analysis meeting ENIGMA BRCA2 PP4 thresholds was identified. PP4 was therefore not assessed. Details ▾Hide ▴
Rule
ENIGMA BRCA2 v1.2 PP4 uses multifactorial likelihood data only
Still missing
- No multifactorial likelihood ratio meeting PP4 thresholds was identified
Sources
BS2 No individual-level evidence meeting the ENIGMA BRCA2 BS2 point-based framework was identified. BS2 was therefore not assessed. Details ▾Hide ▴
Rule
ENIGMA BRCA2 v1.2 BS2 requires point-based evidence in the absence of Fanconi anemia features
Still missing
- No qualifying adult observations or point-based BS2 evidence was identified
Sources
BS3 No well-established functional study showing no damaging effect, and no ENIGMA Table 9 benign assignment, was identified for this variant. BS3 was therefore not assessed. Details ▾Hide ▴
Rule
ENIGMA BRCA2 v1.2 BS3 requires well-established benign functional evidence or a Table 9 code assignment
Evidence considered
- No matching benign functional assignment in ENIGMA Table 9
Still missing
- No variant-specific BS3-supporting functional evidence was identified
Sources
vcep_s_p_e_c_i_f_i_c_a_t_i_o_n_s___t_a_b_l_e_9___v_1___2___2_0_2_4___1_1___1_8
BS4 No quantitative lack-of-segregation analysis meeting ENIGMA BRCA2 BS4 thresholds was identified. BS4 was therefore not assessed. Details ▾Hide ▴
Rule
ENIGMA BRCA2 v1.2 BS4 requires quantitative non-segregation evidence
Still missing
- No segregation likelihood ratio supporting BS4 was identified
Sources
BP5 No multifactorial likelihood analysis meeting ENIGMA BRCA2 BP5 thresholds was identified. BP5 was therefore not assessed. Details ▾Hide ▴
Rule
ENIGMA BRCA2 v1.2 BP5 uses multifactorial likelihood data only
Still missing
- No multifactorial likelihood ratio supporting BP5 was identified
Sources
Not applicable · 14· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 is not applicable because this is a protein truncating variant, not a missense variant or a same-splice-consequence comparison against a previously classified pathogenic variant. Details ▾Hide ▴
Rule
ENIGMA BRCA2 v1.2 PS1 applies to same amino acid substitution or same splicing consequence contexts
Evidence considered
- Variant type is nonsense
Sources
PS2 N/APS2 is not applicable under the ENIGMA BRCA2 specification. Details ▾Hide ▴
PM1 N/APM1 is not applicable under the ENIGMA BRCA2 specification. Details ▾Hide ▴
PM4 N/APM4 is not applicable under the ENIGMA BRCA2 specification. Details ▾Hide ▴
PM6 N/APM6 is not applicable under the ENIGMA BRCA2 specification. Details ▾Hide ▴
PP2 N/APP2 is not applicable under the ENIGMA BRCA2 specification. Details ▾Hide ▴
PP3 N/APP3 is not applicable because this is a nonsense variant rather than a missense, in-frame, silent, or non-canonical intronic variant evaluated by the ENIGMA BRCA2 in silico rules. SpliceAI predicts no significant splice impact with a maximum delta score of 0.00. Details ▾Hide ▴
Rule
ENIGMA BRCA2 v1.2 PP3 applies to specified missense/in-frame/splice-prediction contexts
Evidence considered
- Variant type is nonsense
- SpliceAI max delta score 0.00
Sources
PP5 N/APP5 is not applicable under the ENIGMA BRCA2 specification. Details ▾Hide ▴
BP1 N/ABP1 is not applicable because this is a nonsense variant rather than a silent, missense, or in-frame variant. Details ▾Hide ▴
Rule
ENIGMA BRCA2 v1.2 BP1 applies to silent, missense, or in-frame variants outside clinically important domains with no splice impact
Evidence considered
- Variant type is nonsense
Sources
BP2 N/ABP2 is not applicable under the ENIGMA BRCA2 specification. Details ▾Hide ▴
BP3 N/ABP3 is not applicable under the ENIGMA BRCA2 specification. Details ▾Hide ▴
BP4 N/ABP4 is not applicable because this is a nonsense variant rather than a missense, in-frame, silent, or non-canonical intronic variant assessed under the ENIGMA BRCA2 BP4 framework. SpliceAI predicts no significant splice impact with a maximum delta score of 0.00. Details ▾Hide ▴
Rule
ENIGMA BRCA2 v1.2 BP4 applies to specified missense/in-frame/silent/intronic contexts with no predicted splice impact
Evidence considered
- Variant type is nonsense
- SpliceAI max delta score 0.00
Sources
BP6 N/ABP6 is not applicable under the ENIGMA BRCA2 specification. Details ▾Hide ▴
BP7 N/ABP7 is not applicable because this is a nonsense variant rather than a silent or intronic variant, or a missense/in-frame variant in the specific RNA-only contexts defined by ENIGMA BRCA2. SpliceAI predicts no significant splice impact with a maximum delta score of 0.00. Details ▾Hide ▴
Rule
ENIGMA BRCA2 v1.2 BP7 applies to silent, intronic, and selected RNA-only contexts
Evidence considered
- Variant type is nonsense
- SpliceAI max delta score 0.00
Sources
Identifiers
- Gene
- BRCA2
- Transcript
- NM_000059.4
- Coding (HGVS c.)
- NM_000059.4:c.2830A>T
- Protein (HGVS p.)
- NP_000050.3:p.(Lys944Ter)
- GRCh38
- chr13:32337185 A>T
- GRCh37
- chr13:32911322 A>T
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
6 / 1,613,668 alleles
AF 3.72e-06 · 0 homozygotes · FAF 7.9e-07
gnomAD v2.1
3 / 282,020 alleles
AF 1.06e-05 · 0 homozygotes
By genetic ancestry
gnomAD v4.1
AF 3.7e-06 · 6 / 1,613,668 alleles · 0 hom · FAF 7.9e-07
| African/African American1 / 74,928 | 1.3e-05 |
| South Asian1 / 91,010 | 1.1e-05 |
| European (non-Finnish)4 / 1,179,850 | 3.4e-06 |
0 alternate alleles recorded in 7 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish.
gnomAD v2.1
AF 1.1e-05 · 3 / 282,020 alleles · 0 hom
| African/African American1 / 24,868 | 4e-05 |
| South Asian1 / 30,514 | 3.3e-05 |
| European (non-Finnish)1 / 128,752 | 7.8e-06 |
0 alternate alleles recorded in 5 other groups: Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 3.71824e-06; MAF= 0.00037%, 6/1613668 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 1.33461e-05; MAF= 0.00133%, 1/74928 alleles, homozygotes = 0); grpmax FAF= 7.9e-07.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.06375e-05; MAF= 0.00106%, 3/282020 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 4.02123e-05; MAF= 0.00402%, 1/24868 alleles, homozygotes = 0).
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 N/APP3 is not applicable because this is a nonsense variant rather than a missense, in-frame, silent, or non-canonical intronic variant evaluated by the ENIGMA BRCA2 in silico rules. SpliceAI predicts no significant splice impact with a maximum delta score of 0.00. Details ▾Hide ▴
Rule
ENIGMA BRCA2 v1.2 PP3 applies to specified missense/in-frame/splice-prediction contexts
Evidence considered
- Variant type is nonsense
- SpliceAI max delta score 0.00
Sources
BP4 N/ABP4 is not applicable because this is a nonsense variant rather than a missense, in-frame, silent, or non-canonical intronic variant assessed under the ENIGMA BRCA2 BP4 framework. SpliceAI predicts no significant splice impact with a maximum delta score of 0.00. Details ▾Hide ▴
Rule
ENIGMA BRCA2 v1.2 BP4 applies to specified missense/in-frame/silent/intronic contexts with no predicted splice impact
Evidence considered
- Variant type is nonsense
- SpliceAI max delta score 0.00
Sources
BP7 N/ABP7 is not applicable because this is a nonsense variant rather than a silent or intronic variant, or a missense/in-frame variant in the specific RNA-only contexts defined by ENIGMA BRCA2. SpliceAI predicts no significant splice impact with a maximum delta score of 0.00. Details ▾Hide ▴
Rule
ENIGMA BRCA2 v1.2 BP7 applies to silent, intronic, and selected RNA-only contexts
Evidence considered
- Variant type 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).
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
6 / 1,613,668 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Captured SpliceAI source record
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/variation/51355/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/13-32911322-A-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr13-32337185-A-T?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000059.4%3Ac.2830…
- OncoKB ↗www.oncokb.org/gene/BRCA2/K944*
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=123599696
- 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
This variant is present in gnomAD v4.1 (AF= 3.71824e-06; MAF= 0.00037%, 6/1613668 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 1.33461e-05; MAF= 0.00133%, 1/74928 alleles, homozygotes = 0); grpmax FAF= 7.9e-07.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.06375e-05; MAF= 0.00106%, 3/282020 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 4.02123e-05; MAF= 0.00402%, 1/24868 alleles, homozygotes = 0).
ClinVar
This variant has been reported in ClinVar as Pathogenic (37 clinical laboratories) and as pathogenic (1 clinical laboratory) and as Pathogenic by Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) (expert panel).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional
OncoKB classifies this variant as Likely Oncogenic; biological effect: Likely Loss-of-function.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV66450359, n = 4 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.