About CHEK2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
CHEK2 c.1375+2T>G, p.?
Classification
Likely pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.
Likely pathogenic.A likely 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 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: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PVS1Very strong
PVS1 · very strong
Variant NM_007194.4:c.1375+2T>G alters the canonical +2 donor position of an intron in CHEK2. Workspace normalization places it at an internal splice donor with predicted protein consequence p.?; CHEK2 loss of function is an established disease mechanism, and this type of canonical splice-site variant is expected to disrupt normal splicing.
PM2Supporting
PM2 · supporting
The variant is absent from gnomAD v2.1 and present only once in gnomAD v4.1 (1/1,432,544 alleles; AF about 6.98e-07; no homozygotes), which supports rarity consistent with PM2 at supporting strength.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Likely pathogenic
ACMG/AMP with CHEK2 VCEP framework context; applied criteria PVS1_VeryStrong + PM2_Supporting
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
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
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 ↗
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
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 · 3 not met · 10 not assessed · 13 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
The variant affects the canonical +2 donor position of CHEK2 and is expected to disrupt normal splicing, which supports PVS1 in a loss-of-function disease mechanism context.
The reviewed CHEK2 framework mode is VCEP and the case workspace points to the CHEK2 ClinGen specification as the primary interpretive authority, although the local criterion table was not populated.
Population data support rarity: the variant is absent from gnomAD v2.1 and observed only once in gnomAD v4.1 with no homozygotes, supporting PM2 at supporting strength.
No convincing variant-specific case-control, segregation, de novo, or functional RNA evidence for this exact allele was identified in the reviewed workspace, so no additional criteria were added.
Using ACMG/AMP combining rules, PVS1 plus PM2_Supporting supports a Likely Pathogenic classification.
No criteria match.
Met · 2
PVS1 Very strongVariant NM_007194.4:c.1375+2T>G alters the canonical +2 donor position of an intron in CHEK2. Workspace normalization places it at an internal splice donor with predicted protein consequence p.?; CHEK2 loss of function is an established disease mechanism, and this type of canonical splice-site variant is expected to disrupt normal splicing. Details ▾Hide ▴
Evidence considered
- Canonical splice donor +2 variant: NM_007194.4:c.1375+2T>G
- SpliceAI max delta score 0.99
- CHEK2 truncating variants are disease-associated in reviewed CHEK2 literature
Still missing
- Gene-specific CHEK2 VCEP rule text was not present in the local vcep_db files, so strength assignment is based on the workspace plus the available CHEK2 VCEP framework metadata rather than a locally cached criterion table.
- No RNA study for this exact variant was present in the workspace.
Sources
PM2 SupportingThe variant is absent from gnomAD v2.1 and present only once in gnomAD v4.1 (1/1,432,544 alleles; AF about 6.98e-07; no homozygotes), which supports rarity consistent with PM2 at supporting strength. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1
- Present in gnomAD v4.1 at 1/1,432,544 alleles with 0 homozygotes
Sources
Not met · 3 · evaluated, threshold not reached
PS4 Reviewed literature supports risk from CHEK2 truncating variants as a class, but the workspace did not provide variant-specific case-control enrichment for this exact c.1375+2T>G allele. Details ▾Hide ▴
Evidence considered
- CHEK2 truncating variant risk literature is not specific to c.1375+2T>G
Still missing
- Variant-specific case-control or prevalence data not available
Sources
BA1 Population frequency is far below any BA1 threshold. Details ▾Hide ▴
BS1 Population frequency is far below benign stand-alone/supporting thresholds. Details ▾Hide ▴
Not assessed · 10 · no assessment recorded
PS2 No de novo data were assembled in the reviewed workspace. Details ▾Hide ▴
Still missing
- Proband parental testing / de novo confirmation not available
PS3 No well-validated functional assay or variant-specific RNA assay for NM_007194.4:c.1375+2T>G was present in the workspace. Details ▾Hide ▴
PM6 No assumed de novo evidence was available in the workspace. Details ▾Hide ▴
Still missing
- Parental studies not available
PP1 No segregation data were provided in the assembled case workspace. Details ▾Hide ▴
Still missing
- Family segregation evidence not available
PP4 No phenotype-specific proband data were included in the workspace to support PP4. Details ▾Hide ▴
Still missing
- Clinical phenotype and family history details not available
BS2 No evidence of occurrence in healthy adults at a rate inconsistent with disease was assembled in the workspace. Details ▾Hide ▴
Still missing
- Cohort-level unaffected adult evidence not available
BS3 No functional evidence demonstrating lack of damaging effect for this exact variant was present in the workspace. Details ▾Hide ▴
Still missing
- Benign functional or RNA assay not available
BS4 No non-segregation data were provided. Details ▾Hide ▴
Still missing
- Family segregation data not available
BP2 No phase data with another pathogenic variant were assembled. Details ▾Hide ▴
Still missing
- Phase testing not available
BP5 No alternate molecular explanation for the phenotype was provided in the workspace. Details ▾Hide ▴
Still missing
- Broader phenotype/genotype context not available
Not applicable · 13· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 is for the same amino acid change as a known pathogenic missense variant and does not apply to this splice-site variant. Details ▾Hide ▴
No further detail was recorded.
PM1 N/APM1 is generally used for mutational hot spots or critical functional domains in protein-coding sequence, not for this canonical splice-site variant. Details ▾Hide ▴
No further detail was recorded.
PM3 N/APM3 is for recessive disorders with trans observations and is not applicable to CHEK2-related cancer predisposition in this context. Details ▾Hide ▴
Evidence considered
- CHEK2-related cancer predisposition in the workspace is modeled as autosomal dominant
Sources
PM4 N/APM4 is not used here because the primary effect is splice disruption already captured by PVS1 rather than an in-frame protein length change. Details ▾Hide ▴
No further detail was recorded.
PM5 N/APM5 applies to novel missense changes at an amino acid residue and does not apply to this splice-site variant. Details ▾Hide ▴
No further detail was recorded.
PP2 N/APP2 concerns missense constraint / missense mechanism and is not applicable to this splice-site variant. Details ▾Hide ▴
No further detail was recorded.
PP3 N/AAlthough SpliceAI predicts strong splice impact, this evidence is not additionally counted because the canonical splice-site effect is already captured under PVS1. Details ▾Hide ▴
PP5 N/APP5 is not used for classification here. Details ▾Hide ▴
No further detail was recorded.
BP1 N/ABP1 concerns missense variation and is not applicable to this splice-site variant. Details ▾Hide ▴
No further detail was recorded.
BP3 N/ABP3 concerns in-frame indels in repetitive regions and does not apply to this splice-site SNV. Details ▾Hide ▴
No further detail was recorded.
BP4 N/AComputational evidence is not benign; SpliceAI predicts strong splice disruption, so BP4 is not applicable. Details ▾Hide ▴
BP6 N/ABP6 is not used for classification here. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 does not apply because this is not a silent/intronic variant predicted to have no splice impact; instead it alters a canonical +2 donor base with strong splice-disruption prediction. Details ▾Hide ▴
Identifiers
- Gene
- CHEK2
- Transcript
- NM_007194.4
- Coding (HGVS c.)
- NM_007194.4:c.1375+2T>G
- Protein (HGVS p.)
- NP_009125.1:p.?
- GRCh38
- chr22:28695125 A>C
- GRCh37
- chr22:29091113 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 |
|---|
Statements
No population statements were recorded.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 N/AAlthough SpliceAI predicts strong splice impact, this evidence is not additionally counted because the canonical splice-site effect is already captured under PVS1. Details ▾Hide ▴
BP4 N/AComputational evidence is not benign; SpliceAI predicts strong splice disruption, so BP4 is not applicable. Details ▾Hide ▴
BP7 N/ABP7 does not apply because this is not a silent/intronic variant predicted to have no splice impact; instead it alters a canonical +2 donor base with strong splice-disruption prediction. Details ▾Hide ▴
Statement
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.99).
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
Captured gnomAD v4.1 source record
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
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/2018612/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/22-29091113-A-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr22-28695125-A-C?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_007194.4%3Ac.1375…
- OncoKB ↗www.oncokb.org/gene/CHEK2
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.99).
Somatic
This variant has not previously been reported in somatic cancers (COSMIC).