NM_007194.4:c.1375+2T>G

CHEK2 · NP_009125.1:p.? · NM_007194.4

GRCh37: chr22:29091113 A>C · GRCh38: chr22:28695125 A>C

Gene: CHEK2 Transcript: NM_007194.4

Final call

Likely Pathogenic

PVS1 PM2

Variant details

Gene

CHEK2

Transcript

NM_007194.4

Protein

NP_009125.1:p.?

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

Final determination:

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	Met	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.	cspec spliceai PMID:21876083
PS1	N/A	PS1 is for the same amino acid change as a known pathogenic missense variant and does not apply to this splice-site variant.
PS2	Not assessed	No de novo data were assembled in the reviewed workspace.
PS3	Not assessed	No well-validated functional assay or variant-specific RNA assay for NM_007194.4:c.1375+2T>G was present in the workspace.
PS4	Not met	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.	PMID:21876083
PM1	N/A	PM1 is generally used for mutational hot spots or critical functional domains in protein-coding sequence, not for this canonical splice-site variant.
PM2	Met	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.	gnomad_v2 gnomad_v4
PM3	N/A	PM3 is for recessive disorders with trans observations and is not applicable to CHEK2-related cancer predisposition in this context.	cspec
PM4	N/A	PM4 is not used here because the primary effect is splice disruption already captured by PVS1 rather than an in-frame protein length change.
PM5	N/A	PM5 applies to novel missense changes at an amino acid residue and does not apply to this splice-site variant.
PM6	Not assessed	No assumed de novo evidence was available in the workspace.
PP1	Not assessed	No segregation data were provided in the assembled case workspace.
PP2	N/A	PP2 concerns missense constraint / missense mechanism and is not applicable to this splice-site variant.
PP3	N/A	Although SpliceAI predicts strong splice impact, this evidence is not additionally counted because the canonical splice-site effect is already captured under PVS1.	spliceai
PP4	Not assessed	No phenotype-specific proband data were included in the workspace to support PP4.
PP5	N/A	PP5 is not used for classification here.
BA1	Not met	Population frequency is far below any BA1 threshold.	gnomad_v4
BS1	Not met	Population frequency is far below benign stand-alone/supporting thresholds.	gnomad_v4
BS2	Not assessed	No evidence of occurrence in healthy adults at a rate inconsistent with disease was assembled in the workspace.
BS3	Not assessed	No functional evidence demonstrating lack of damaging effect for this exact variant was present in the workspace.
BS4	Not assessed	No non-segregation data were provided.
BP1	N/A	BP1 concerns missense variation and is not applicable to this splice-site variant.
BP2	Not assessed	No phase data with another pathogenic variant were assembled.
BP3	N/A	BP3 concerns in-frame indels in repetitive regions and does not apply to this splice-site SNV.
BP4	N/A	Computational evidence is not benign; SpliceAI predicts strong splice disruption, so BP4 is not applicable.	spliceai
BP5	Not assessed	No alternate molecular explanation for the phenotype was provided in the workspace.
BP6	N/A	BP6 is not used for classification here.
BP7	N/A	BP7 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.	spliceai

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