About CHEK2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
CHEK2 c.-6-8T>G, p.?
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 CHEK2 VCEP v1.0.0. 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: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and is present only 3 times in 1,612,954 alleles in gnomAD v4.1 (overall AF 1.85994e-06, 0.00019%; highest observed population AF 1.6001e-05, 0.00160%), which is well below a 0.1% rarity threshold and supports rarity.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Available computational evidence supports no meaningful splice effect. SpliceAI showed a maximum delta score of 0.10, which is below commonly used thresholds for significant splice disruption and argues against an abnormal splicing effect.
Recorded classification: Uncertain significance
Hereditary Breast, Ovarian and Pancreatic Cancer Specification v1.0.0 lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP4 supporting; combination = 1 supporting + 1 supporting benign, which maps to VUS because the evidence is conflicting.
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
3 / 1,612,954 alleles
gnomAD v4.1: 3 / 1,612,954 alleles. Recorded AF 1.85994e-06. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
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 CHEK2 VCEP v1.0.0, with the data and sources behind each one.
28 criteria with recorded statuses: 2 met · 6 not met · 12 not assessed · 8 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
The CHEK2 NM_007194.4:c.-6-8T>G (NP_009125.1:p.?) variant has been reported in ClinVar as likely benign by a single clinical laboratory.
This variant is absent from gnomAD v2.1 and is present only 3 times in 1,612,954 alleles in gnomAD v4.1 (overall AF 1.85994e-06; highest observed population AF 1.6001e-05), supporting rarity but not a benign frequency threshold.
In silico splicing analysis does not support a meaningful splice effect, with SpliceAI showing a maximum delta score of 0.10.
No criteria match.
Met · 2
PM2 SupportingThis variant is absent from gnomAD v2.1 and is present only 3 times in 1,612,954 alleles in gnomAD v4.1 (overall AF 1.85994e-06, 0.00019%; highest observed population AF 1.6001e-05, 0.00160%), which is well below a 0.1% rarity threshold and supports rarity. Details ▾Hide ▴
Rule
Generic ACMG rarity evidence applied at supporting strength for an autosomal dominant cancer-predisposition gene.
Evidence considered
- Absent from gnomAD v2.1.
- Present at extremely low frequency in gnomAD v4.1 with no homozygotes.
Still missing
- The CHEK2 CSPEC was available but did not provide a structured PM2 rule payload in the reviewed materials.
Sources
BP4 SupportingAvailable computational evidence supports no meaningful splice effect. SpliceAI showed a maximum delta score of 0.10, which is below commonly used thresholds for significant splice disruption and argues against an abnormal splicing effect. Details ▾Hide ▴
Rule
Generic ACMG BP4 applied using computational evidence supporting no impact on splicing.
Evidence considered
- SpliceAI DS_AG 0.05
- DS_AL 0.10
- DS_DG 0.00
- DS_DL 0.03
- max delta score 0.10.
Still missing
- No additional benign computational predictors were available for this noncoding variant in the reviewed files.
Sources
Not met · 6 · evaluated, threshold not reached
PS4 Available evidence does not show an increased prevalence of this variant in affected individuals compared with controls. Only a single ClinVar submission was identified, which is insufficient for a case-enrichment assertion. Details ▾Hide ▴
Rule
PS4 requires significant enrichment in affected individuals.
Evidence considered
- ClinVar shows one clinical laboratory submission.
- No affected-versus-control enrichment data identified.
Still missing
- No case-control data or multiple unrelated affected probands were identified for this variant.
Sources
PM1 This variant is located in a non-canonical intronic region rather than a known CHEK2 mutational hotspot or well-established critical functional domain with low benign variation. Details ▾Hide ▴
Rule
PM1 requires location in a mutational hotspot or critical functional domain without benign variation.
Evidence considered
- Variant is intronic with no defined protein-domain involvement.
Still missing
- No site-specific hotspot or constrained splice-region evidence was identified for this position.
PP3 Available computational evidence does not support a damaging effect on splicing. SpliceAI showed a maximum delta score of 0.10, which does not indicate a significant splice impact. Details ▾Hide ▴
Rule
PP3 requires multiple computational lines of evidence supporting a deleterious effect.
Evidence considered
- SpliceAI DS_AG 0.05
- DS_AL 0.10
- DS_DG 0.00
- DS_DL 0.03
- max delta score 0.10.
Still missing
- No additional computational evidence supporting pathogenic splicing impact was identified.
Sources
BA1 The observed population frequency is far below a stand-alone benign threshold. The highest observed gnomAD v4.1 population frequency is 1.6001e-05 (0.00160%), which is well below 1%. Details ▾Hide ▴
Rule
BA1 requires allele frequency above a stand-alone benign threshold.
Evidence considered
- Highest observed subpopulation AF in gnomAD v4.1 is 1.6001e-05.
Sources
BS1 The observed population frequency is too low for benign strong evidence. The highest observed gnomAD v4.1 population frequency is 1.6001e-05 (0.00160%), which is well below a 0.3% benign threshold. Details ▾Hide ▴
Rule
BS1 requires allele frequency greater than expected for the disorder.
Evidence considered
- Highest observed subpopulation AF in gnomAD v4.1 is 1.6001e-05.
Sources
BP7 Although SpliceAI does not predict a significant splice effect, BP7 was not applied because the reviewed evidence does not provide the additional contextual support typically used for this criterion in a noncoding intronic variant. Details ▾Hide ▴
Rule
BP7 was considered but not applied for this intronic variant based on the available evidence and framework detail.
Evidence considered
- SpliceAI max delta score 0.10.
- No structured CHEK2 CSPEC BP7 rule was available in the reviewed materials.
Still missing
- No additional noncoding-specific framework detail or other supporting evidence for BP7 application was identified.
Sources
Not assessed · 12 · no assessment recorded
PS2 No confirmed de novo occurrence data were identified for this variant. Details ▾Hide ▴
Rule
PS2 requires a confirmed de novo occurrence in a patient with the disease and no family history.
Evidence considered
- ClinVar record reviewed without de novo evidence.
Still missing
- No trio-based parentage-confirmed de novo report was identified.
Sources
PS3 No well-established functional study was identified showing that this variant damages CHEK2 function or causes abnormal splicing. Details ▾Hide ▴
Rule
PS3 requires well-established functional studies supportive of a damaging effect.
Evidence considered
- No variant-specific functional assay identified in the reviewed evidence.
Still missing
- No patient RNA study was identified.
- No minigene or other validated functional assay was identified for this variant.
Sources
PM6 No assumed de novo occurrence without parental confirmation was identified for this variant. Details ▾Hide ▴
Rule
PM6 requires an assumed de novo occurrence without confirmation of paternity and maternity.
Evidence considered
- ClinVar record reviewed without de novo evidence.
Still missing
- No report of an unconfirmed de novo occurrence was identified.
Sources
PP1 No segregation data were identified for this variant. Details ▾Hide ▴
Rule
PP1 requires cosegregation with disease in multiple affected family members.
Evidence considered
- No segregation information available in the reviewed evidence.
Still missing
- No informative family cosegregation study was identified.
Sources
PP4 No phenotype information was provided that would allow assessment of whether the clinical presentation is highly specific for CHEK2-related disease. Details ▾Hide ▴
Rule
PP4 requires a phenotype or family history highly specific for a disease with a single genetic etiology.
Evidence considered
- Disease context known
- but no patient-specific phenotype supplied.
Still missing
- No case phenotype or family history details were available for review.
Sources
PP5 This criterion was not used because assertion-based evidence without accessible supporting data is not considered sufficient for independent classification. Details ▾Hide ▴
Rule
PP5 is generally not applied when primary evidence can be reviewed directly.
Evidence considered
- ClinVar contains a single submitter classification.
Sources
BS2 Available population data do not establish this variant as observed in a context that would support BS2 for CHEK2-related disease. Details ▾Hide ▴
Rule
BS2 requires observation in healthy adults for a disorder with expected full penetrance at an early age.
Evidence considered
- No homozygotes reported in gnomAD v4.1.
Still missing
- No evidence was identified showing this variant in healthy adults at a frequency or clinical context sufficient for BS2.
Sources
BS3 No well-established functional study was identified showing that this variant has no damaging effect on CHEK2 function or splicing. Details ▾Hide ▴
Rule
BS3 requires well-established functional studies showing no damaging effect.
Evidence considered
- No variant-specific benign functional assay identified in the reviewed evidence.
Still missing
- No benign RNA or minigene assay was identified for this variant.
Sources
BS4 No non-segregation data were identified for this variant. Details ▾Hide ▴
Rule
BS4 requires lack of segregation with disease in affected family members.
Evidence considered
- No family non-segregation evidence available in the reviewed evidence.
Still missing
- No informative family study showing lack of segregation was identified.
Sources
BP2 No phase data with another pathogenic variant were identified for this variant. Details ▾Hide ▴
Rule
BP2 requires observation in trans with a pathogenic variant for a dominant disorder or in cis for any inheritance pattern.
Evidence considered
- No allelic phase information available.
Still missing
- No cis/trans observations with another pathogenic variant were identified.
BP5 No alternate molecular explanation for the observed phenotype was provided, so BP5 could not be assessed. Details ▾Hide ▴
Rule
BP5 requires a variant found in a case with an alternate molecular basis for disease.
Evidence considered
- No patient-specific phenotype or alternate genotype information available.
Still missing
- No phenotype-specific alternate diagnostic explanation was available.
BP6 This criterion was not used because assertion-based benign evidence without accessible supporting data is not considered sufficient for independent classification. Details ▾Hide ▴
Rule
BP6 is generally not applied when primary evidence can be reviewed directly.
Evidence considered
- ClinVar contains a single likely benign submission.
Sources
Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis intronic variant is outside the canonical splice ±1,2 positions, and the generic PVS1 assessment concluded that it does not fall into the default null-variant categories used for PVS1. Although loss of function is an established CHEK2 disease mechanism, available evidence does not show that this specific non-canonical intronic change causes loss of function. Details ▾Hide ▴
Rule
Generic PVS1 fallback considered but not applicable for a non-canonical intronic variant outside the default null-variant buckets.
Evidence considered
- CHEK2 loss of function is supported as a disease mechanism at the gene level.
- Variant-specific generic PVS1 scaffold does not support PVS1 application for this non-canonical intronic change.
Still missing
- No RNA or minigene study was identified for this variant.
- No direct evidence was identified that this variant disrupts splicing of the exon containing the start codon.
Sources
PS1 N/AThis variant does not have a defined protein consequence, so there is no basis to assess whether it produces the same amino acid change as an established pathogenic variant. Details ▾Hide ▴
Rule
PS1 applies to variants with the same amino acid change as a known pathogenic variant.
Evidence considered
- Predicted protein consequence is p.?.
PM3 N/APM3 is intended for recessive disorders with pathogenic variants detected in trans, which is not the relevant inheritance framework for CHEK2-related cancer predisposition. Details ▾Hide ▴
Rule
PM3 applies to recessive conditions.
Evidence considered
- CHEK2 CSPEC disease context is autosomal dominant.
Sources
PM4 N/AThis intronic variant does not change protein length and is not an in-frame deletion, insertion, or stop-loss variant. Details ▾Hide ▴
Rule
PM4 applies to protein length changes.
Evidence considered
- Predicted protein consequence is p.?.
PM5 N/AThis variant does not have a defined missense protein consequence, so there is no basis to compare it with other pathogenic missense changes at the same residue. Details ▾Hide ▴
Rule
PM5 applies to novel missense changes at an amino acid residue where another pathogenic missense change has been seen.
Evidence considered
- Predicted protein consequence is p.?.
PP2 N/APP2 is a missense-specific criterion and does not apply to this intronic variant. Details ▾Hide ▴
Rule
PP2 applies to missense variants in genes with a low rate of benign missense variation and where missense is a common disease mechanism.
Evidence considered
- Variant is intronic
- not missense.
BP1 N/ABP1 is a missense-specific criterion and does not apply to this intronic variant. Details ▾Hide ▴
Rule
BP1 applies to missense variants in genes where truncating variants are primarily disease-causing.
Evidence considered
- Variant is intronic
- not missense.
BP3 N/AThis intronic variant is not an in-frame deletion or insertion in a repetitive region. Details ▾Hide ▴
Rule
BP3 applies to in-frame deletions or insertions in repetitive regions without known function.
Evidence considered
- Variant is a single-nucleotide intronic substitution.
Identifiers
- Gene
- CHEK2
- Transcript
- NM_007194.4
- Coding (HGVS c.)
- NM_007194.4:c.-6-8T>G
- Protein (HGVS p.)
- NP_009125.1:p.?
- GRCh38
- chr22:28734735 A>C
- GRCh37
- chr22:29130723 A>C
Gene diagram
Every interpreted variant in CHEK2, mapped onto the exon structure of NM_007194.4. Select a row to find it on the plot.
CHEK2NM_007194.4
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 CHEK2
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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
3 / 1,612,954 alleles
AF 1.86e-06 · 0 homozygotes
gnomAD v2.1
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 1.9e-06 · 3 / 1,612,954 alleles · 0 hom
| Remaining individuals1 / 62,496 | 1.6e-05 |
| African/African American1 / 75,026 | 1.3e-05 |
| European (non-Finnish)1 / 1,179,672 | 8.5e-07 |
0 alternate alleles recorded in 7 other groups: Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.85994e-06; MAF= 0.00019%, 3/1612954 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 1.6001e-05; MAF= 0.00160%, 1/62496 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP4 SupportingAvailable computational evidence supports no meaningful splice effect. SpliceAI showed a maximum delta score of 0.10, which is below commonly used thresholds for significant splice disruption and argues against an abnormal splicing effect. Details ▾Hide ▴
Rule
Generic ACMG BP4 applied using computational evidence supporting no impact on splicing.
Evidence considered
- SpliceAI DS_AG 0.05
- DS_AL 0.10
- DS_DG 0.00
- DS_DL 0.03
- max delta score 0.10.
Still missing
- No additional benign computational predictors were available for this noncoding variant in the reviewed files.
Sources
PP3 Available computational evidence does not support a damaging effect on splicing. SpliceAI showed a maximum delta score of 0.10, which does not indicate a significant splice impact. Details ▾Hide ▴
Rule
PP3 requires multiple computational lines of evidence supporting a deleterious effect.
Evidence considered
- SpliceAI DS_AG 0.05
- DS_AL 0.10
- DS_DG 0.00
- DS_DL 0.03
- max delta score 0.10.
Still missing
- No additional computational evidence supporting pathogenic splicing impact was identified.
Sources
BP7 Although SpliceAI does not predict a significant splice effect, BP7 was not applied because the reviewed evidence does not provide the additional contextual support typically used for this criterion in a noncoding intronic variant. Details ▾Hide ▴
Rule
BP7 was considered but not applied for this intronic variant based on the available evidence and framework detail.
Evidence considered
- SpliceAI max delta score 0.10.
- No structured CHEK2 CSPEC BP7 rule was available in the reviewed materials.
Still missing
- No additional noncoding-specific framework detail or other supporting evidence for BP7 application was identified.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.10).
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
3 / 1,612,954 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/522546466
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/491583/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/22-29130723-A-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr22-28734735-A-C?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_007194.4%3Ac.-6-8…
- OncoKB ↗www.oncokb.org/gene/CHEK2/?
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=CHEK2+c.-6-8T%3EG
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= 1.85994e-06; MAF= 0.00019%, 3/1612954 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 1.6001e-05; MAF= 0.00160%, 1/62496 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant has been reported in ClinVar as Likely benign (1 clinical laboratory).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.10).
Somatic
This variant has not previously been reported in somatic cancers (COSMIC).