About BRCA2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRCA2 c.7977-1G>C, p.?
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
PVS1Strong
PVS1 · strong
This canonical splice acceptor variant in BRCA2 exon 18 is assigned PVS1_Strong (RNA) by the ENIGMA BRCA2 specification. ENIGMA notes that variants at this splice site show leaky splicing, which reduces the weight from very strong to strong; RNA evidence summarized for this variant shows exon 18 deletion and exon 17/18 deletion, supporting an abnormal loss-of-function transcript effect.
PM5Strong
PM5 · strong
ENIGMA BRCA2 Table 4 designates exon 18 as eligible for PM5_Strong (PTC). Because this canonical splice variant is assigned PVS1 at exon 18 and ENIGMA applies PM5_PTC at this exon, additional strong pathogenic weight is supported.
PP4Moderate
PP4 · moderate
In the BRCA2 clinical-history likelihood-ratio dataset, this variant has an LR of 7.223 across 7 probands. This exceeds the ENIGMA PP4_Moderate threshold of 4.3 and is below the PP4_Strong threshold of 18.7, supporting PP4 at moderate strength.
PP5Supporting
PP5 · supporting
Expert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen 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 final-classification framework (Table 3 criteria-combination rules via CSPEC/VCEP override).
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
5 / 1,612,350 alleles
gnomAD v4.1: 5 / 1,612,350 alleles. Recorded AF 3.10106e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.11663e-06; MAF= 0.00071%, 2/281032 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.56023e-05; MAF= 0.00156%, 2/128186 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.
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
Not assessed
No COSMIC evidence statement is recorded in this case.
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.
28 criteria with recorded statuses: 4 met · 6 not met · 6 not assessed · 12 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.7977-1G>C (p.?) variant has been reported in ClinVar as Pathogenic, including a Pathogenic expert-panel classification from ENIGMA.
This variant is present at a very low frequency in population databases, with gnomAD v2.1 AF 7.11663e-06 (2/281032 alleles) and gnomAD v4.1 AF 3.10106e-06 (5/1612350 alleles), which is below benign frequency thresholds.
RNA studies summarized in the ENIGMA BRCA2 materials reported abnormal splicing for this variant, including exon 18 deletion and exon 17/18 deletion, and ENIGMA Table 4 assigns PVS1_Strong (RNA) at this splice acceptor because variants at this site show leaky splicing.
Computational splicing analysis is also strongly abnormal, with a SpliceAI maximum delta score of 0.95, consistent with splice disruption, although this prediction is not counted separately because splice-impact evidence is already captured under PVS1 in the ENIGMA framework.
In the BRCA2 clinical-history likelihood-ratio dataset, this variant had an LR of 7.223 across 7 probands, which meets the ENIGMA threshold for PP4 at moderate strength.
No criteria match.
Met · 4
PVS1 StrongThis canonical splice acceptor variant in BRCA2 exon 18 is assigned PVS1_Strong (RNA) by the ENIGMA BRCA2 specification. ENIGMA notes that variants at this splice site show leaky splicing, which reduces the weight from very strong to strong; RNA evidence summarized for this variant shows exon 18 deletion and exon 17/18 deletion, supporting an abnormal loss-of-function transcript effect. Details ▾Hide ▴
Rule
ENIGMA BRCA2 Table 4 assigns c.7977-1G>C as PVS1_Strong (RNA).
Evidence considered
- BRCA2 loss of function is an established disease mechanism in the ENIGMA framework.
- ENIGMA Table 4 lists c.7977-1G>C as PVS1_Strong (RNA) with reduced strength because of leaky splicing at this site.
- Splicing evidence summarized for this variant includes exon 18 deletion and exon 17/18 deletion.
Sources
cspec ↗pvs1_gene_contextpvs1_variant_assessmentvcep_specifications_table4_v1_2_2024_11_18vcep_humu_40_1557_s001PMID:16211554 ↗
PM5 StrongENIGMA BRCA2 Table 4 designates exon 18 as eligible for PM5_Strong (PTC). Because this canonical splice variant is assigned PVS1 at exon 18 and ENIGMA applies PM5_PTC at this exon, additional strong pathogenic weight is supported. Details ▾Hide ▴
Rule
ENIGMA BRCA2 Table 4: exon 18 is PM5_Strong (PTC) eligible.
Evidence considered
- ENIGMA Table 4 lists exon 18 with PM5_Strong (PTC) applicability.
- The variant is a canonical splice variant at the exon 18 acceptor.
Sources
cspec ↗vcep_specifications_table4_v1_2_2024_11_18
PP4 ModerateIn the BRCA2 clinical-history likelihood-ratio dataset, this variant has an LR of 7.223 across 7 probands. This exceeds the ENIGMA PP4_Moderate threshold of 4.3 and is below the PP4_Strong threshold of 18.7, supporting PP4 at moderate strength. Details ▾Hide ▴
Rule
ENIGMA PP4_Moderate based on LR 7.223.
Evidence considered
- Clinical-history LR 7.223215162037175.
- N probands = 7.
- PP4_Moderate threshold >= 4.3
- PP4_Strong threshold >= 18.7.
Sources
Not met · 6 · evaluated, threshold not reached
PS3 Available functional evidence is RNA splicing evidence rather than a qualifying protein functional assay. Under the ENIGMA BRCA2 specification, abnormal mRNA-only evidence for this variant is captured under PVS1(RNA), and this variant is not listed in the curated BRCA2 protein functional assay table for PS3. Details ▾Hide ▴
Evidence considered
- RNA studies are summarized for this splice-site variant.
- The curated ENIGMA Table 9 protein functional assay file did not provide a PS3 assignment for c.7977-1G>C.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18vcep_specifications_table9_v1_2_2024_11_18vcep_humu_40_1557_s001PMID:16211554 ↗
PM2 This variant is not absent from population databases. It is present in gnomAD v2.1 at AF 7.11663e-06 (2/281032 alleles) and in gnomAD v4.1 at AF 3.10106e-06 (5/1612350 alleles), so the ENIGMA requirement for PM2_Supporting of absence from controls is not met. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 total AF 7.11663e-06
- 2 alleles.
- gnomAD v4.1 total AF 3.10106e-06
- 5 alleles.
Sources
BA1 The observed population frequency is far below the ENIGMA BA1 threshold. gnomAD v4.1 shows grpmax FAF 1.24e-06, which is below the BA1 cutoff of 0.001, so BA1 is not met. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 grpmax FAF 1.24e-06.
- BA1 threshold FAF > 0.001.
Sources
BS1 The observed population frequency is below the ENIGMA BS1 thresholds. gnomAD v4.1 shows grpmax FAF 1.24e-06, which is below the BS1_Supporting threshold of 2e-05 and the BS1 threshold of 1e-04, so BS1 is not met. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 grpmax FAF 1.24e-06.
- BS1_Supporting threshold FAF > 2e-05.
- BS1 threshold FAF > 1e-04.
Sources
BS3 No functional evidence showing normal transcript or normal BRCA2 function was identified for this variant. The available RNA evidence supports abnormal splicing rather than a benign effect, and this variant is not assigned BS3 in the curated ENIGMA functional assay table. Details ▾Hide ▴
Evidence considered
- RNA evidence supports abnormal splicing.
- No BS3 assignment was identified in the ENIGMA functional assay table.
Sources
BP5 The clinical-history likelihood ratio does not support BP5. The BRCA2 clinical-history LR for this variant is 7.223, which is above the BP5 benign thresholds of 0.48, 0.23, and 0.05, so BP5 is not met. Details ▾Hide ▴
Evidence considered
- Clinical-history LR 7.223215162037175.
- BP5 thresholds require LR <= 0.48
- <= 0.23
- or <= 0.05 depending on strength.
Sources
Not assessed · 6 · no assessment recorded
PS1 No independently reviewed pathogenic comparator variant with the same established splicing effect was identified to support PS1. Available evidence supports direct splice disruption for this variant, but the retrieved materials do not establish a separate PS1 comparator-based application. Details ▾Hide ▴
Evidence considered
- ENIGMA allows PS1 for variants with the same predicted or demonstrated splicing impact as a previously classified pathogenic variant.
Still missing
- A qualifying previously classified pathogenic or likely pathogenic comparator variant with the same splicing outcome was not identified in the reviewed materials.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
PS4 This variant has been reported in affected individuals, but no qualifying case-control analysis with an odds ratio and confidence interval meeting the ENIGMA PS4 threshold was identified. The available multifactorial and classification resources do not substitute for a direct PS4 case-control showing. Details ▾Hide ▴
Evidence considered
- ClinVar reports a pathogenic expert-panel classification.
- Multifactorial datasets classify the variant as pathogenic but do not provide a direct ENIGMA PS4 case-control application in the reviewed materials.
Still missing
- No eligible case-control dataset with p-value and odds ratio meeting ENIGMA PS4 requirements was identified.
Sources
PM3 No data were identified showing this variant in trans with another pathogenic BRCA2 variant in an individual with a phenotype consistent with BRCA2-related Fanconi anemia. PM3 therefore cannot be assessed from the available evidence. Details ▾Hide ▴
Still missing
- No qualifying recessive disease phenotype or phase-confirmed trans observation was identified.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
PP1 No quantitative segregation data were identified for this variant. Without a segregation likelihood ratio meeting ENIGMA thresholds, PP1 cannot be applied. Details ▾Hide ▴
Still missing
- No family segregation likelihood ratio or pedigree-based segregation analysis was identified.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
BS2 No evidence was identified showing this variant in individuals scored under the ENIGMA BS2 recessive-disease framework. BS2 therefore cannot be assessed from the available evidence. Details ▾Hide ▴
Still missing
- No qualifying observations in the ENIGMA BRCA2 Fanconi-anemia-based BS2 framework were identified.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
BS4 No quantitative non-segregation data were identified for this variant. Without a segregation likelihood ratio at or below the ENIGMA BS4 thresholds, BS4 cannot be applied. Details ▾Hide ▴
Still missing
- No pedigree-based non-segregation likelihood ratio was identified.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴
PS2 N/AThis criterion is not applicable in the ENIGMA BRCA2 specification for this review context, and no de novo data were provided. Details ▾Hide ▴
Sources
PM1 N/APM1 is not used as a separate criterion in the ENIGMA BRCA2 framework for this variant type. This canonical splice-site variant is evaluated through splice-specific criteria rather than domain hotspot evidence. Details ▾Hide ▴
Sources
PM4 N/APM4 is not applicable because this is not a protein length-changing in-frame deletion, insertion, or stop-loss variant. Details ▾Hide ▴
Sources
PM6 N/AThis criterion is not applicable in the ENIGMA BRCA2 specification for this review context, and no assumed de novo observation was provided. Details ▾Hide ▴
Sources
PP2 N/APP2 is not applicable in the ENIGMA BRCA2 specification for this variant. Details ▾Hide ▴
Sources
PP3 N/ASpliceAI predicts a strong splice effect for this variant with a maximum delta score of 0.95, but PP3 is not separately applied because the same splice-effect evidence is already captured by PVS1 in the ENIGMA framework. The generic PVS1 scaffold for this case also advises against double-counting PP3 for canonical splice variants assessed by PVS1. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score 0.95.
- Canonical splice variant assessed under PVS1.
Sources
BP1 N/ABP1 does not apply because this is not a missense, silent, or in-frame coding variant evaluated under the BRCA2 protein/domain bioinformatic framework. This variant is a canonical splice-site change. Details ▾Hide ▴
Sources
BP2 N/ABP2 is not applicable in the ENIGMA BRCA2 specification for this variant. Details ▾Hide ▴
Sources
BP3 N/ABP3 is not applicable because this is not an in-frame insertion or deletion in a repetitive region. Details ▾Hide ▴
Sources
BP4 N/ABP4 does not apply because this variant is at a native splice acceptor position and computational evidence supports splice disruption rather than no effect. SpliceAI shows a maximum delta score of 0.95, which is far above the ENIGMA no-impact threshold of 0.1. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score 0.95.
- BayesDel score 0.308409.
Sources
BP6 N/ABP6 is not applicable in this ENIGMA BRCA2 framework. Details ▾Hide ▴
Sources
BP7 N/ABP7 does not apply because this is a canonical splice-site variant at the exon 18 acceptor, not a silent or deep intronic variant with evidence for no splicing effect. Available RNA and computational evidence support splice disruption instead of a benign splice outcome. Details ▾Hide ▴
Evidence considered
- Canonical splice acceptor position.
- SpliceAI max delta score 0.95.
- RNA summaries show abnormal splicing.
Sources
Identifiers
- Gene
- BRCA2
- Transcript
- NM_000059.3
- Coding (HGVS c.)
- NM_000059.3:c.7977-1G>C
- Protein (HGVS p.)
- NP_000050.2:p.?
- GRCh38
- chr13:32363178 G>C
- GRCh37
- chr13:32937315 G>C
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
5 / 1,612,350 alleles
AF 3.1e-06 · 0 homozygotes · FAF 1.24e-06
gnomAD v2.1
2 / 281,032 alleles
AF 7.12e-06 · 0 homozygotes
By genetic ancestry
gnomAD v4.1
AF 3.1e-06 · 5 / 1,612,350 alleles · 0 hom · FAF 1.2e-06
| European (non-Finnish)5 / 1,179,106 | 4.2e-06 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 7.1e-06 · 2 / 281,032 alleles · 0 hom
| European (non-Finnish)2 / 128,186 | 1.6e-05 |
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 3.10106e-06; MAF= 0.00031%, 5/1612350 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 4.2405e-06; MAF= 0.00042%, 5/1179106 alleles, homozygotes = 0); grpmax FAF= 1.24e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.11663e-06; MAF= 0.00071%, 2/281032 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.56023e-05; MAF= 0.00156%, 2/128186 alleles, homozygotes = 0).
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 N/ASpliceAI predicts a strong splice effect for this variant with a maximum delta score of 0.95, but PP3 is not separately applied because the same splice-effect evidence is already captured by PVS1 in the ENIGMA framework. The generic PVS1 scaffold for this case also advises against double-counting PP3 for canonical splice variants assessed by PVS1. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score 0.95.
- Canonical splice variant assessed under PVS1.
Sources
BP4 N/ABP4 does not apply because this variant is at a native splice acceptor position and computational evidence supports splice disruption rather than no effect. SpliceAI shows a maximum delta score of 0.95, which is far above the ENIGMA no-impact threshold of 0.1. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score 0.95.
- BayesDel score 0.308409.
Sources
BP7 N/ABP7 does not apply because this is a canonical splice-site variant at the exon 18 acceptor, not a silent or deep intronic variant with evidence for no splicing effect. Available RNA and computational evidence support splice disruption instead of a benign splice outcome. Details ▾Hide ▴
Evidence considered
- Canonical splice acceptor position.
- SpliceAI max delta score 0.95.
- RNA summaries show abnormal splicing.
Sources
Statement
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.95). BayesDel score = 0.308409.
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
5 / 1,612,350 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 ↗
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/38132/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/13-32937315-G-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr13-32363178-G-C?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000059.3%3Ac.7977…
- OncoKB ↗www.oncokb.org/gene/BRCA2/?
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=123595977
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= 3.10106e-06; MAF= 0.00031%, 5/1612350 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 4.2405e-06; MAF= 0.00042%, 5/1179106 alleles, homozygotes = 0); grpmax FAF= 1.24e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.11663e-06; MAF= 0.00071%, 2/281032 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.56023e-05; MAF= 0.00156%, 2/128186 alleles, homozygotes = 0).
ClinVar
This variant has been reported in ClinVar as Pathogenic (20 clinical laboratories) and as Pathogenic by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel).
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.95). BayesDel score = 0.308409.
Somatic
This variant has previously been reported in somatic cancers (COSMIC; COSV104701362, n = 1 times).