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.1 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.2 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.3 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.4
Final classification
Likely Pathogenic
PVS1PM2
CHEK2
c.1375+2T>G
p.?
This variant
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.
ACMG/AMP with CHEK2 VCEP framework context; applied criteria PVS1_VeryStrong + PM2_Supporting
Classification rationale
PVS1PM2
Likely Pathogenic
CHEK2 c.1375+2T>G
PVS1 + PM2
→
Likely Pathogenic
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.
Gene diagram
· NM_007194.4 · variants mapped to exon structure
CHEK2
NM_007194.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 13 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
PVS1
very_strong
review
Pathogenic
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.
Canonical splice donor +2 variant: NM_007194.4:c.1375+2T>GSpliceAI max delta score 0.99CHEK2 truncating variants are disease-associated in reviewed CHEK2 literature
PM2
supporting
review
Pathogenic
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.
Absent from gnomAD v2.1Present in gnomAD v4.1 at 1/1,432,544 alleles with 0 homozygotes
Assessed · not applied
· 3 not met · 10 not assessed
Pathogenic
PS2
No de novo data were assembled in the reviewed workspace.
PS3
No well-validated functional assay or variant-specific RNA assay for NM_007194.4:c.1375+2T>G was present in the workspace.
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.
PM6
No assumed de novo evidence was available in the workspace.
PP1
No segregation data were provided in the assembled case workspace.
PP4
No phenotype-specific proband data were included in the workspace to support PP4.
Benign
BA1
Population frequency is far below any BA1 threshold.
BS1
Population frequency is far below benign stand-alone/supporting thresholds.
BS2
No evidence of occurrence in healthy adults at a rate inconsistent with disease was assembled in the workspace.
BS3
No functional evidence demonstrating lack of damaging effect for this exact variant was present in the workspace.
BS4
No non-segregation data were provided.
BP2
No phase data with another pathogenic variant were assembled.
BP5
No alternate molecular explanation for the phenotype was provided in the workspace.
N/A · 13
PS1 · PM1 · PM3 · PM4 · PM5 · PP2 · PP3 · PP5 · BP1 · BP3 · BP4 · BP6 · BP7
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
Allele frequency by ancestry
three datasets · side by side
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.99).
Functional
No data
No calibrated functional assay or RNA evidence was identified for this variant.
COSMIC
Somatic evidence
COSMIC
This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant cancer hotspot.
Literature · how each cited paper was used
2papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.
Splicing in action: assessing disease causing sequence changes.
Found
Structured finding pending for this record — see source link.
Applied to
→PVS1
very_strong
Risk of breast cancer in women with a CHEK2 mutation with and without a family h
Found
Structured finding pending for this record — see source link.
Applied to
→PVS1
very_strong
Sources & reference links