NM_007194.4:c.1376-23G>C

CHEK2 · NP_009125.1:p.? · NM_007194.4

GRCh37: chr22:29090128 C>G · GRCh38: chr22:28694140 C>G

Gene: CHEK2 Transcript: NM_007194.4

Final call

VUS

PM2 supporting BP4 supporting benign

Variant details

Gene

CHEK2

Transcript

NM_007194.4

Protein

NP_009125.1:p.?

gnomAD AF

1.798228145866939e-05 (v4.1)

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

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).

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

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	N/A	This 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.	pvs1_variant_assessment spliceai
PS1	N/A	This is an intronic substitution with no amino acid change; PS1 (same amino acid change as established pathogenic variant) cannot be assessed.
PS2	Not met	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.
PS3	Not met	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.
PS4	Not met	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.
PS5	Not met	No reputable source has recently reported this variant as pathogenic with unavailable supporting evidence.
PM1	Not met	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.
PM2	Met	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.	gnomad_v2 gnomad_v4
PM5	N/A	PM5 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.	pm5_candidates
PM6	Not met	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.
PP1	Not met	No cosegregation data are available for this variant in families with CHEK2-related cancer. No published family studies document this variant tracking with disease.
PP2	N/A	PP2 applies to missense variants in genes with a low rate of benign missense variation. This is an intronic variant, not a missense change.
PP3	Not met	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.	spliceai
PP4	Not met	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.
PP5	Not met	No reputable source has recently reported this variant as pathogenic with unavailable supporting evidence.
BA1	Not met	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.	gnomad_v2 gnomad_v4
BS1	Not met	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.	gnomad_v2 gnomad_v4
BS2	Not met	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.	gnomad_v2 gnomad_v4
BS3	Not met	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.
BS4	Not met	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.
BP1	N/A	BP1 applies to missense variants in genes where a truncating mechanism primarily causes disease. This is an intronic variant, not a missense change.
BP2	Not met	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.
BP4	Met	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.	spliceai
BP5	Not met	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.
BP6	Not met	No reputable source has recently reported this variant as benign with unavailable supporting evidence.
BP7	N/A	BP7 applies to synonymous (silent) variants with no predicted splicing impact. This is a deep intronic substitution, not a synonymous coding variant.
BP3	N/A	BP3 applies to in-frame insertions/deletions in repetitive regions; this is a substitution variant.
PM3	N/A	PM3 applies to recessive disorders with a second pathogenic variant observed in trans. CHEK2-associated cancer predisposition is autosomal dominant; PM3 is not applicable.
PM4	N/A	PM4 applies to protein length-changing variants (in-frame deletions/insertions, stop-loss). This is a substitution variant.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.