About BRCA2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRCA2 c.7970A>C, p.(Lys2657Thr)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
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: 1
Benign evidence criteria: 0
Pathogenic criteria applied · 1
PS3Strong
PS3 · strong
In a calibrated BRCA2 functional study summarized in ENIGMA Table 9, c.7970A>C (p.(Lys2657Thr)) showed protein function similar to pathogenic control variants, supporting a damaging effect on protein function. This meets PS3 at strong strength.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
ENIGMA BRCA1 and BRCA2 Specification v1.2.0 Table 3 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
1 / 1,614,028 alleles
gnomAD v4.1: 1 / 1,614,028 alleles. Recorded AF 6.19568e-07. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
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 did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. BRCA2, a tumor suppressor involved in the DNA damage response, is mutated in various cancer types.
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: 1 met · 10 not met · 6 not assessed · 11 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.7970A>C (p.Lys2657Thr, K2657T) variant has been reported in ClinVar, where the ClinGen ENIGMA expert panel classified it as uncertain significance and other submitters reported likely pathogenic and uncertain significance assertions.
This variant is absent from gnomAD v2.1 and is present once in gnomAD v4.1 (1/1614028 alleles overall; highest observed frequency 1/59996 in Admixed American individuals), supporting rarity but not complete absence from population databases.
In a calibrated BRCA2 functional study summarized by the ENIGMA BRCA1/2 specification, p.Lys2657Thr showed protein function similar to pathogenic control variants, supporting PS3 at strong strength.
Computational evidence predicts no significant splice impact (SpliceAI max delta score 0.01), while the missense prediction profile is mixed under ENIGMA thresholds (REVEL 0.799; BayesDel 0.270216), so PP3 and BP4 are not independently met.
A BRCA2 clinical-history likelihood ratio of 1.188967663938105 from 1 proband falls in the ENIGMA neutral zone (>0.48 and <2.08), so neither PP4 nor BP5 is supported by the reviewed multifactorial clinical-history data.
No criteria match.
Met · 1
PS3 StrongIn a calibrated BRCA2 functional study summarized in ENIGMA Table 9, c.7970A>C (p.(Lys2657Thr)) showed protein function similar to pathogenic control variants, supporting a damaging effect on protein function. This meets PS3 at strong strength. Details ▾Hide ▴
Evidence considered
- ENIGMA Table 9 row for c.7970A>C classified as PS3 Strong
- Richardson 2021 functional evidence
Sources
Not met · 10 · evaluated, threshold not reached
PVS1 This variant is a missense substitution, p.(Lys2657Thr), rather than a nonsense, frameshift, initiation-loss, exon-deletion, or canonical +/-1,2 splice variant. SpliceAI predicts no significant splice impact (max delta score 0.01), so available evidence does not support a loss-of-function mechanism for PVS1. Details ▾Hide ▴
Evidence considered
- Missense consequence p.(Lys2657Thr)
- SpliceAI max delta 0.01
Still missing
- No RNA study showing an abnormal transcript consequence was identified for this variant.
Sources
PM2 This variant is absent from gnomAD v2.1 but is present in gnomAD v4.1 at 1/1,614,028 alleles overall, with highest observed frequency 1/59,996 in the Admixed American population. ENIGMA PM2_Supporting requires absence from population controls, so available data do not show complete absence. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 absent
- gnomAD v4.1 total AF 6.195679381026847e-07
Still missing
- Direct gnomAD v3.1 review was not available in the reviewed sources.
Sources
PP3 This missense variant lies within the BRCA2 DNA-binding domain, but ENIGMA PP3 for missense variants in this region requires BayesDel no-AF >=0.30 or predicted splice impact with SpliceAI >=0.2. The observed BayesDel score is 0.270216 and SpliceAI max delta score is 0.01; REVEL is 0.799 but is not the ENIGMA BRCA2 decision threshold for PP3. Therefore PP3 is not met. Details ▾Hide ▴
Evidence considered
- Protein position 2657 within BRCA2 DNA-binding domain
- BayesDel 0.270216
- SpliceAI max delta 0.01
- REVEL 0.799
Sources
PP4 The BRCA2 clinical-history likelihood ratio for c.7970A>C is 1.188967663938105 from 1 proband. This is below the ENIGMA PP4 supporting threshold of 2.08, so available multifactorial clinical-history evidence does not support PP4. Details ▾Hide ▴
Evidence considered
- Clinical-history LR 1.188967663938105
- N probands 1
Still missing
- No additional validated multifactorial LR source exceeding the PP4 threshold was identified.
Sources
BA1 Available population data do not meet the ENIGMA BA1 threshold. The variant is absent from gnomAD v2.1 and has total allele frequency 6.195679381026847e-07 in gnomAD v4.1, far below the BA1 threshold of 0.001. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 absent
- gnomAD v4.1 total AF 6.195679381026847e-07
Sources
BS1 Available population data do not meet ENIGMA BS1 thresholds. The highest observed population allele frequency is 1.666777785185679e-05 in Admixed American individuals, which is below the BS1 supporting threshold of 0.00002 and below the strong threshold of 0.0001. Details ▾Hide ▴
Evidence considered
- Highest observed subpopulation AF 1.666777785185679e-05 in gnomAD v4.1
Still missing
- No qualifying filter allele frequency above ENIGMA BS1 thresholds was identified.
Sources
BS3 Available calibrated functional evidence supports a damaging effect rather than a neutral effect for this variant. Therefore BS3 is not met. Details ▾Hide ▴
Evidence considered
- ENIGMA Table 9 assigns PS3 Strong
- not BS3
Still missing
- No calibrated benign functional result was identified for this variant.
Sources
BP1 This missense variant is located within the BRCA2 DNA-binding domain (aa 2481-3186). Although SpliceAI predicts no significant splice impact (max delta score 0.01), ENIGMA BP1_Strong requires a missense or silent variant outside a clinically important functional domain, so BP1 is not met. Details ▾Hide ▴
Evidence considered
- Protein position 2657 within BRCA2 DNA-binding domain
- SpliceAI max delta 0.01
Sources
BP4 This missense variant is within the BRCA2 DNA-binding domain, and SpliceAI predicts no significant splice impact (max delta score 0.01). However, ENIGMA BP4 for missense variants in a clinically important domain requires BayesDel no-AF <=0.18, and the observed BayesDel score is 0.270216; REVEL is 0.799 but is not the ENIGMA BRCA2 decision threshold for BP4. Therefore BP4 is not met. Details ▾Hide ▴
Evidence considered
- BayesDel 0.270216
- SpliceAI max delta 0.01
- REVEL 0.799
Sources
BP5 The BRCA2 clinical-history likelihood ratio for c.7970A>C is 1.188967663938105 from 1 proband. This is above the BP5 supporting threshold of 0.48 and falls within the ENIGMA neutral zone (>0.48 and <2.08), so BP5 is not met. Details ▾Hide ▴
Evidence considered
- Clinical-history LR 1.188967663938105
- N probands 1
Still missing
- No additional validated multifactorial LR source below BP5 thresholds was identified.
Sources
Not assessed · 6 · no assessment recorded
PS1 No previously classified pathogenic or likely pathogenic variant encoding the same amino acid change was identified in the reviewed sources, so PS1 was not established. Details ▾Hide ▴
PS4 No case-control study or exact-variant enrichment statistic meeting ENIGMA PS4 requirements was identified for this variant. The reviewed ENIGMA posterior probability and multifactorial tables did not provide an exact-variant PS4 result. Details ▾Hide ▴
Evidence considered
- Reviewed ENIGMA ST7 and HUMU multifactorial resources without an exact PS4 result
Still missing
- No odds ratio
- confidence interval
- and p-value specific to this variant were identified.
Sources
PM3 No evidence was identified that this variant was observed in trans with another pathogenic BRCA2 variant in an individual with BRCA2-related Fanconi anemia features, so PM3 could not be assessed. Details ▾Hide ▴
Evidence considered
- No qualifying PM3 case data identified
Still missing
- No phase-confirmed co-occurrence data in a BRCA2-related Fanconi anemia context were identified.
Sources
PP1 No quantitative co-segregation analysis or segregation likelihood ratio meeting ENIGMA PP1 thresholds was identified for this variant. Details ▾Hide ▴
Evidence considered
- No PP1 segregation evidence identified
Still missing
- No family segregation dataset or likelihood ratio >=2.08 was identified.
Sources
BS2 No qualifying co-occurrence or unaffected-adult evidence meeting the ENIGMA BS2 point system was identified for this variant. Details ▾Hide ▴
Evidence considered
- No BS2-qualifying observations identified
Still missing
- No phase-defined observations with sufficient phenotype information were identified.
Sources
BS4 No quantitative lack-of-segregation analysis or segregation likelihood ratio meeting ENIGMA BS4 thresholds was identified for this variant. Details ▾Hide ▴
Evidence considered
- Reviewed ENIGMA multifactorial resources without a qualifying BS4 result
Still missing
- No family-based likelihood ratio <=0.48 was identified.
Sources
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PS2 N/AThis criterion is not calibrated for BRCA1/2-related cancers in the ENIGMA BRCA2 specification. Details ▾Hide ▴
PM1 N/APM1 is not used as an independent criterion in the ENIGMA BRCA2 specification because domain information is incorporated into the BRCA2 bioinformatic framework. Details ▾Hide ▴
PM4 N/APM4 is not applicable because this is a missense substitution and the ENIGMA BRCA2 specification does not use PM4 for this context. Details ▾Hide ▴
PM5 N/AIn the ENIGMA BRCA2 specification, PM5 is adapted for protein-truncating variants and is not used here for this missense substitution. Details ▾Hide ▴
Evidence considered
- ENIGMA PM5 framework is PTC-specific
Sources
cspec ↗vcep_specifications_table4_v1_2_2024_11_18
PM6 N/AThis criterion is not calibrated for BRCA1/2-related cancers in the ENIGMA BRCA2 specification. Details ▾Hide ▴
PP2 N/APP2 is not used for BRCA2 in the ENIGMA specification because benign missense variation is too common for this code to be informative. Details ▾Hide ▴
PP5 N/APP5 is not for use in this VCEP framework. Details ▾Hide ▴
BP2 N/ABP2 is not used independently in the ENIGMA BRCA2 framework and is only considered within the BS2 context. Details ▾Hide ▴
BP3 N/ABP3 is not applicable in the ENIGMA BRCA2 specification. Details ▾Hide ▴
BP6 N/ABP6 is not for use in this VCEP framework. Details ▾Hide ▴
BP7 N/AThis is a missense variant within a clinically important functional domain, and no RNA-only benign assay result was identified. Although SpliceAI predicts no significant splice impact (max delta score 0.01), BP7 is not applicable in this context. Details ▾Hide ▴
Evidence considered
- Missense variant in BRCA2 DNA-binding domain
- SpliceAI max delta 0.01
Still missing
- No RNA-only benign splicing study was identified for this variant.
Sources
Identifiers
- Gene
- BRCA2
- Transcript
- NM_000059.3
- Coding (HGVS c.)
- NM_000059.3:c.7970A>C
- Protein (HGVS p.)
- NP_000050.2:p.(Lys2657Thr)
- GRCh38
- chr13:32362687 A>C
- GRCh37
- chr13:32936824 A>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
1 / 1,614,028 alleles
AF 6.2e-07 · 0 homozygotes
gnomAD v2.1
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 6.2e-07 · 1 / 1,614,028 alleles · 0 hom
| Admixed American1 / 59,996 | 1.7e-05 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish).
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 6.19568e-07; MAF= 0.00006%, 1/1614028 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 1.66678e-05; MAF= 0.00167%, 1/59996 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 This missense variant lies within the BRCA2 DNA-binding domain, but ENIGMA PP3 for missense variants in this region requires BayesDel no-AF >=0.30 or predicted splice impact with SpliceAI >=0.2. The observed BayesDel score is 0.270216 and SpliceAI max delta score is 0.01; REVEL is 0.799 but is not the ENIGMA BRCA2 decision threshold for PP3. Therefore PP3 is not met. Details ▾Hide ▴
Evidence considered
- Protein position 2657 within BRCA2 DNA-binding domain
- BayesDel 0.270216
- SpliceAI max delta 0.01
- REVEL 0.799
Sources
BP4 This missense variant is within the BRCA2 DNA-binding domain, and SpliceAI predicts no significant splice impact (max delta score 0.01). However, ENIGMA BP4 for missense variants in a clinically important domain requires BayesDel no-AF <=0.18, and the observed BayesDel score is 0.270216; REVEL is 0.799 but is not the ENIGMA BRCA2 decision threshold for BP4. Therefore BP4 is not met. Details ▾Hide ▴
Evidence considered
- BayesDel 0.270216
- SpliceAI max delta 0.01
- REVEL 0.799
Sources
BP7 N/AThis is a missense variant within a clinically important functional domain, and no RNA-only benign assay result was identified. Although SpliceAI predicts no significant splice impact (max delta score 0.01), BP7 is not applicable in this context. Details ▾Hide ▴
Evidence considered
- Missense variant in BRCA2 DNA-binding domain
- SpliceAI max delta 0.01
Still missing
- No RNA-only benign splicing study was identified for this variant.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.799. BayesDel score = 0.270216.
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
1 / 1,614,028 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/441298/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/13-32936824-A-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr13-32362687-A-C?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000059.3%3Ac.7970…
- OncoKB ↗www.oncokb.org/gene/BRCA2/K2657T
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=BRCA2+c.7970A%3EC
- 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= 6.19568e-07; MAF= 0.00006%, 1/1614028 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 1.66678e-05; MAF= 0.00167%, 1/59996 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant has been reported in ClinVar as Likely pathogenic (1 clinical laboratory) and as Uncertain significance (1 clinical laboratory) and as Uncertain Significance by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.799. BayesDel score = 0.270216.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. BRCA2, a tumor suppressor involved in the DNA damage response, is mutated in various cancer types.
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.