About CHEK2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
CHEK2 c.1376-23G>C, 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 present at extremely low frequency in population databases: gnomAD v2.1 AF = 6.42e-5 (0.0064%, 15/233,494 alleles) and gnomAD v4.1 AF = 1.80e-5 (0.0018%, 27/1,501,478 alleles), both well below the PM2 threshold of 0.1%. The grpmax filtering allele frequency is 0.03% (v2.1) and 0.02% (v4.1), also below 0.1%. All observed alleles are restricted to the South Asian population. No homozygotes observed. Absent from gnomAD-Canada. Absent from ClinVar.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence suggest no impact on gene product. SpliceAI predicts no splicing impact for this intronic variant (max delta score = 0.00; all acceptor and donor gain/loss scores are 0.00). REVEL and BayesDel are not applicable to intronic variants, and the absence of any predicted splice alteration is consistent with a benign computational profile.
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 benign; combination = 1 supporting + 1 supporting benign, which maps to VUS.
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
27 / 1,501,478 alleles
gnomAD v4.1: 27 / 1,501,478 alleles. Recorded AF 1.79823e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 6.42415e-05; MAF= 0.00642%, 15/233494 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000494495; MAF= 0.04945%, 15/30334 alleles, homozygotes = 0); grpmax FAF= 0.00030425.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
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
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
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.
29 criteria with recorded statuses: 2 met · 18 not met · 0 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
NM_007194.4:c.1376-23G>C is a deep intronic variant in CHEK2 intron 12, located 23 bases upstream of exon 13.
This variant is present at extremely low frequency in population databases: gnomAD v2.1 allele frequency = 0.0064% (15/233,494 alleles) and gnomAD v4.1 allele frequency = 0.0018% (27/1,501,478 alleles), with all observations restricted to the South Asian population and no homozygotes observed (PM2_Supporting).
Computational splicing analysis with SpliceAI predicts no impact on splicing (max delta score = 0.00; all four delta scores for acceptor gain, acceptor loss, donor gain, and donor loss are 0.00), consistent with a benign computational profile (BP4_Supporting).
The variant does not fall into any PVS1 null-variant category (not a nonsense, frameshift, or canonical splice variant), and SpliceAI confirms no predicted cryptic splice alteration.
No functional studies, segregation data, de novo observations, case-control data, or ClinVar classifications are available for this variant.
Applying the generic ACMG/AMP 2015 final combination rules (PMID:25741868), the evidence profile consists of one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4). With only one supporting criterion on each side, the evidence is indeterminate, resulting in a classification of Variant of Uncertain Significance (VUS).
No criteria match.
Met · 2
PM2 SupportingThis variant is present at extremely low frequency in population databases: gnomAD v2.1 AF = 6.42e-5 (0.0064%, 15/233,494 alleles) and gnomAD v4.1 AF = 1.80e-5 (0.0018%, 27/1,501,478 alleles), both well below the PM2 threshold of 0.1%. The grpmax filtering allele frequency is 0.03% (v2.1) and 0.02% (v4.1), also below 0.1%. All observed alleles are restricted to the South Asian population. No homozygotes observed. Absent from gnomAD-Canada. Absent from ClinVar. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: AF=6.42e-5 (15/233
- 494)
- 0 homozygotes
- gnomAD v4.1: AF=1.80e-5 (27/1
- 501
- 478)
- grpmax FAF <0.1% in both datasets.
Sources
BP4 SupportingMultiple lines of computational evidence suggest no impact on gene product. SpliceAI predicts no splicing impact for this intronic variant (max delta score = 0.00; all acceptor and donor gain/loss scores are 0.00). REVEL and BayesDel are not applicable to intronic variants, and the absence of any predicted splice alteration is consistent with a benign computational profile. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00
- all four delta scores (acceptor gain
- acceptor loss
- donor gain
- donor loss) = 0.00. Pangolin splice gain = 0.01
- splice loss = -0.0.
Sources
Not met · 18 · evaluated, threshold not reached
PS2 No evidence of a de novo occurrence of this variant in a proband with CHEK2-related cancer phenotype. No published trio studies or clinical reports document de novo status. Details ▾Hide ▴
Evidence considered
- Exploratory literature and database search found no de novo observations.
Still missing
- No de novo data available — requires trio sequencing or parental testing.
PS3 No published functional studies (in vitro or in vivo) directly assessing the impact of NM_007194.4:c.1376-23G>C on CHEK2 splicing, expression, or kinase activity were identified. Details ▾Hide ▴
Evidence considered
- Exploratory search found no variant-specific functional data
- only gene-level functional literature exists.
Still missing
- No functional data — minigene splicing assay or patient RNA studies would be required.
PS4 No case-control study comparing the frequency of this variant in CHEK2-related cancer cohorts versus the general population is available. PS4 requires a statistically significant enrichment in affected individuals. Details ▾Hide ▴
Evidence considered
- gnomAD population frequency data alone insufficient for PS4
- no case-control dataset identified.
Still missing
- No case-control study available for this variant.
PM1 This is a deep intronic variant (c.1376-23G>C) not located in a known mutational hot spot or critical functional domain. Cancer Hotspots database shows no significance for this residue, and the variant is not in a known CHEK2 functional domain. Details ▾Hide ▴
Evidence considered
- Hotspots: residue_significant=false
- exact_variant_listed=no. Intronic position outside functional domains.
PM6 No de novo observation of this variant has been reported without confirmation of paternity and maternity. PM6 requires a de novo finding where both parental relationships are unconfirmed. Details ▾Hide ▴
Evidence considered
- No de novo reports identified in any database or literature search.
Still missing
- No de novo data available.
PP1 No cosegregation data are available for this variant in families with CHEK2-related cancer. No published family studies document this variant tracking with disease. Details ▾Hide ▴
Evidence considered
- No segregation data identified in ClinVar or published literature.
Still missing
- No family segregation studies available.
PP3 Multiple lines of computational evidence do not support a deleterious effect. SpliceAI predicts no splicing impact (max delta score = 0.00). REVEL and BayesDel are not available for this intronic variant. No in silico tool supports pathogenicity. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00 (acceptor_gain=0
- acceptor_loss=0
- donor_gain=0
- donor_loss=0)
- REVEL/BayesDel not applicable to intronic variant.
Sources
PP4 No patient phenotype or family history data specific to this variant are available for review. PP4 requires that the patient's phenotype or family history is highly specific for CHEK2-related cancer predisposition. Details ▾Hide ▴
Evidence considered
- No patient-level clinical data provided.
Still missing
- No patient phenotype or family history data available.
PP5 No reputable source has recently reported this variant as pathogenic with unavailable supporting evidence. Details ▾Hide ▴
Evidence considered
- No ClinVar or literature assertion of pathogenicity.
BA1 The maximum allele frequency observed for this variant is 0.0495% (gnomAD v2.1 South Asian population), which is well below the BA1 threshold of 1% (or 5% by generic ACMG/AMP). This variant is not a common polymorphism. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 max subpop AF = 0.0495% (SAS
- 15/30
- 334)
- v4.1 max subpop AF = 0.0292% (SAS
- 26/89
- 040). Both far below BA1 threshold.
Sources
BS1 The maximum allele frequency of 0.0495% (gnomAD v2.1 SAS) is below the BS1 threshold of 0.3% for CHEK2-related cancer predisposition. The variant is too rare to meet BS1. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 max AF = 0.0495% (SAS)
- v4.1 max AF = 0.0292% (SAS). Both below 0.3% BS1 threshold.
Sources
BS2 No evidence that this variant has been observed in a healthy adult individual in a manner inconsistent with pathogenic contribution (e.g., homozygous state, or in trans with a pathogenic variant for a recessive disorder). CHEK2 is autosomal dominant; no homozygous individuals observed. Details ▾Hide ▴
Evidence considered
- No homozygotes in gnomAD
- no co-occurrence data available.
Still missing
- No homozygous or in-trans observations.
Sources
BS3 No well-established functional studies demonstrate that this variant has no deleterious effect on CHEK2 splicing or protein function. BS3 requires experimental evidence of a benign functional impact, which is absent. Details ▾Hide ▴
Evidence considered
- No variant-specific functional studies identified.
Still missing
- No functional benign assay data for this variant.
BS4 No family segregation data are available to demonstrate that this variant does not segregate with disease in affected family members. BS4 requires documented lack of cosegregation. Details ▾Hide ▴
Evidence considered
- No segregation or non-segregation data in published literature or ClinVar.
Still missing
- No family data — negative segregation would need to be documented.
BP2 No evidence that this variant has been observed in cis with a known pathogenic CHEK2 variant in a patient. BP2 requires documented co-occurrence in cis with a pathogenic variant. Details ▾Hide ▴
Evidence considered
- No cis phasing data available in ClinVar or published literature.
Still missing
- No cis/trans phasing data available.
BP5 No evidence that this variant has been found in a case with an alternative molecular basis for disease. BP5 requires the observation of this variant in an individual with a confirmed alternate genetic cause. Details ▾Hide ▴
Evidence considered
- No data on co-occurrence with alternate molecular diagnoses.
Still missing
- No observation with an alternate molecular basis.
BP6 No reputable source has recently reported this variant as benign with unavailable supporting evidence. Details ▾Hide ▴
Evidence considered
- No ClinVar or literature assertion of benign classification.
PS5 No reputable source has recently reported this variant as pathogenic with unavailable supporting evidence. Details ▾Hide ▴
Evidence considered
- No ClinVar or literature assertion of pathogenicity found.
Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis deep intronic variant (c.1376-23G>C, intron 12) does not fall into any PVS1 null-variant category (nonsense, frameshift, canonical ±1,2 splice consensus). SpliceAI predicts no splicing impact (max delta = 0.00). The generic PVS1 framework does not apply to non-null, non-canonical-splice intronic variants. Details ▾Hide ▴
Evidence considered
- Variant is intronic with SpliceAI max delta 0.00
- PVS1 variant bucket is 'other' and apply_generic_pvs1_framework is false.
Sources
pvs1_variant_assessmentspliceai ↗
PS1 N/AThis is an intronic substitution with no amino acid change; PS1 (same amino acid change as established pathogenic variant) cannot be assessed. Details ▾Hide ▴
Evidence considered
- Intronic variant — no protein consequence.
PM3 N/APM3 applies to recessive disorders with a second pathogenic variant observed in trans. CHEK2-associated cancer predisposition is autosomal dominant; PM3 is not applicable. Details ▾Hide ▴
Evidence considered
- CHEK2-related cancer predisposition is autosomal dominant.
PM4 N/APM4 applies to protein length-changing variants (in-frame deletions/insertions, stop-loss). This is a substitution variant. Details ▾Hide ▴
Evidence considered
- Substitution — not a protein length-altering variant.
PM5 N/APM5 requires a different amino acid change at the same residue as an established pathogenic missense variant. This is an intronic variant with no amino acid consequence; PM5 semantics cannot be applied. Details ▾Hide ▴
Evidence considered
- Intronic variant — no protein residue
- pm5_candidates confirms eligible_for_classic_pm5_search=false.
Sources
pm5_candidates
PP2 N/APP2 applies to missense variants in genes with a low rate of benign missense variation. This is an intronic variant, not a missense change. Details ▾Hide ▴
Evidence considered
- Intronic variant — not eligible for PP2 assessment.
BP1 N/ABP1 applies to missense variants in genes where a truncating mechanism primarily causes disease. This is an intronic variant, not a missense change. Details ▾Hide ▴
Evidence considered
- Intronic variant — not eligible for BP1.
BP3 N/ABP3 applies to in-frame insertions/deletions in repetitive regions; this is a substitution variant. Details ▾Hide ▴
Evidence considered
- Substitution — not an in-frame indel.
BP7 N/ABP7 applies to synonymous (silent) variants with no predicted splicing impact. This is a deep intronic substitution, not a synonymous coding variant. Details ▾Hide ▴
Evidence considered
- Intronic variant — not a synonymous change
- BP7 not applicable.
Identifiers
- Gene
- CHEK2
- Transcript
- NM_007194.4
- Coding (HGVS c.)
- NM_007194.4:c.1376-23G>C
- Protein (HGVS p.)
- NP_009125.1:p.?
- GRCh38
- chr22:28694140 C>G
- GRCh37
- chr22:29090128 C>G
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
—
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
27 / 1,501,478 alleles
AF 1.8e-05 · 0 homozygotes · FAF 0.000205
gnomAD v2.1
15 / 233,494 alleles
AF 6.42e-05 · 0 homozygotes · FAF 0.000304
gnomAD-Canada v1.0
0 / 0 alleles
AF 0 · 0 homozygotes · FAF 0
By genetic ancestry
gnomAD v4.1
AF 1.8e-05 · 27 / 1,501,478 alleles · 0 hom · FAF 0.0002
| South Asian26 / 89,040 | 0.00029 |
| Remaining individuals1 / 59,064 | 1.7e-05 |
0 alternate alleles recorded in 8 other groups: Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American, European (non-Finnish).
gnomAD v2.1
AF 6.4e-05 · 15 / 233,494 alleles · 0 hom · FAF 0.0003
| South Asian15 / 30,334 | 0.00049 |
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals.
gnomAD-Canada
AF 0 · 0 / 0 alleles · 0 hom
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.79823e-05; MAF= 0.00180%, 27/1501478 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000292004; MAF= 0.02920%, 26/89040 alleles, homozygotes = 0); grpmax FAF= 0.00020457.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 6.42415e-05; MAF= 0.00642%, 15/233494 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000494495; MAF= 0.04945%, 15/30334 alleles, homozygotes = 0); grpmax FAF= 0.00030425.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP4 SupportingMultiple lines of computational evidence suggest no impact on gene product. SpliceAI predicts no splicing impact for this intronic variant (max delta score = 0.00; all acceptor and donor gain/loss scores are 0.00). REVEL and BayesDel are not applicable to intronic variants, and the absence of any predicted splice alteration is consistent with a benign computational profile. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00
- all four delta scores (acceptor gain
- acceptor loss
- donor gain
- donor loss) = 0.00. Pangolin splice gain = 0.01
- splice loss = -0.0.
Sources
PP3 Multiple lines of computational evidence do not support a deleterious effect. SpliceAI predicts no splicing impact (max delta score = 0.00). REVEL and BayesDel are not available for this intronic variant. No in silico tool supports pathogenicity. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00 (acceptor_gain=0
- acceptor_loss=0
- donor_gain=0
- donor_loss=0)
- REVEL/BayesDel not applicable to intronic variant.
Sources
BP7 N/ABP7 applies to synonymous (silent) variants with no predicted splicing impact. This is a deep intronic substitution, not a synonymous coding variant. Details ▾Hide ▴
Evidence considered
- Intronic variant — not a synonymous change
- BP7 not applicable.
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
27 / 1,501,478 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
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/?term=NM_007194.4%3Ac.1376-23G%3EC
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/22-29090128-C-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr22-28694140-C-G?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_007194.4%3Ac.1376…
- OncoKB ↗www.oncokb.org/gene/CHEK2/?
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=CHEK2+c.1376-23G%3EC
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= 1.79823e-05; MAF= 0.00180%, 27/1501478 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000292004; MAF= 0.02920%, 26/89040 alleles, homozygotes = 0); grpmax FAF= 0.00020457.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 6.42415e-05; MAF= 0.00642%, 15/233494 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000494495; MAF= 0.04945%, 15/30334 alleles, homozygotes = 0); grpmax FAF= 0.00030425.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Somatic
This variant has not previously been reported in somatic cancers (COSMIC).