Variant classification summary

NM_007194.4:c.470T>C

CHEK2 · NP_009125.1:p.(Ile157Thr) · NM_007194.4

GRCh37: chr22:29121087 A>G · GRCh38: chr22:28725099 A>G

Gene: CHEK2 Transcript: NM_007194.4

Final call

VUS

PS3 supporting PM1 moderate BS4 strong

Variant details

Gene

CHEK2

Transcript

NM_007194.4

Protein

NP_009125.1:p.(Ile157Thr)

gnomAD AF

0.00276190381784569 (v4.1)

ClinVar

Likely pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 Supporting: I157T impaired CHEK2 target interactions and the radiation-induced checkpoint, but functional findings were discordant.

2

PM1 Moderate: Ile157 lies in the functional CHEK2 FHA domain, where I157T disrupts target binding.

3

BS4 Strong: mutation-negative affected patients were observed, although cancer phenocopies may mimic lack of segregation.

Final determination: Under generic ACMG/AMP 2015 rules, PS3 Supporting plus PM1 Moderate does not reach a pathogenic combination and BS4 Strong alone does not reach a benign combination, so the result is VUS.

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	Not applicable: PVS1 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not met	Not met: p.Ile157Thr is established only for c.470T>C, with no documented pathogenic alternate nucleotide change producing the same amino-acid substitution.	PMID:11053450 PMID:11298456 PMID:14612911 PMID:12049740
PS2	Not assessed	Not assessed: no proband-specific de novo observation or confirmed maternity and paternity is documented.
PS3	Met	Met at supporting strength: I157T impaired Cdc25A interaction and the radiation-induced S-phase checkpoint, but one study reported wild-type-like activity.	PMID:11298456 PMID:12049740 PMID:11053450
PS4	Not met	Not met: exact-variant prostate-cancer enrichment had OR 2.12 with 95% CI 1.06-4.27, but 2.12 > 5.0? no.	PMID:14612911
PM1	Met	Met: Ile157 is in the functional CHEK2 FHA domain, where I157T disrupts target binding, although no complete domain-wide benign-variation analysis is available.	PMID:11298456 PMID:12049740 cspec
PM2	Not met	Not met: gnomAD v4.1 reports AF 0.0027619, exceeding the PM2 supporting threshold of 0.0001.	gnomad_v4 generic_acmg_combination_rules
PM3	N/A	Not applicable: CHEK2 is autosomal dominant, whereas PM3 is defined for recessive disorders with a pathogenic variant confirmed in trans.	cspec PMID:14612911
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not met	Not met: no different pathogenic missense substitution at CHEK2 residue Ile157 is documented; R145W is at residue 145.	PMID:11298456 PMID:12049740 PMID:11053450 PMID:14612911
PM6	Not assessed	Not assessed: no affected-proband de novo observation without parental confirmation is documented.
PP1	Not met	Not met: segregation was incomplete, with both unaffected carriers and mutation-negative affected patients despite 13/120 hereditary prostate-cancer carriers.	PMID:14612911
PP2	Not met	Not met: gnomAD v4.1 reports p.Ile157Thr at AF 0.27619% with 37 homozygotes, without evidence of a low benign-missense rate for CHEK2.	gnomad_v4 PMID:11298456 PMID:12049740
PP3	Not met	Not met: missense REVEL 0.538 is below the PP3 supporting threshold of >= 0.644 and remains in the indeterminate gray zone.	pvs1_variant_assessment revel
PP4	Not assessed	Not assessed: no patient phenotype or family history is supplied to establish a highly specific single-etiology disease presentation.
PP5	Not met	Not met: ClinVar has zero expert-panel submissions for the exact variant, so ordinary Pathogenic or Likely pathogenic assertions cannot trigger PP5.	clinvar
BA1	Not met	Not met: the highest gnomAD v4.1 frequency is 2.58% in Finnish individuals, below the 5% BA1 threshold.	gnomad_v4 generic_acmg_combination_rules
BS1	Not assessed	Not assessed: Finnish AF is 2.58%, but CHEK2 I157T is low penetrance and no prevalence-penetrance maximum-credible-frequency calculation is available.	gnomad_v4 PMID:14612911 generic_acmg_combination_rules
BS2	N/A	Not applicable: BS2 requires an early-onset, fully penetrant disorder, whereas CHEK2 I157T shows low or incomplete penetrance.	gnomad_v4 PMID:14612911
BS3	Not met	Not met: one study found wild-type-like activity, but two variant-specific studies demonstrated defective substrate interactions and DNA-damage checkpoint function.	PMID:11053450 PMID:11298456 PMID:12049740
BS4	Met	Met: mutation-negative affected patients were observed, although cancer phenocopies may mimic this lack of segregation.	PMID:14612911
BP1	Not met	Not met: I157T disrupts CHEK2 target binding and checkpoint function, demonstrating a recognized missense disease mechanism alongside truncating variants.	PMID:11298456 PMID:12049740 PMID:14612911
BP2	Not assessed	Not assessed: no pathogenic partner allele or cis/trans phase is documented, so neither BP2 pathway can be confirmed.	PMID:14612911 cspec
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: missense REVEL 0.538 is above the BP4 supporting threshold of <= 0.29 and remains in the indeterminate gray zone.	pvs1_variant_assessment revel
BP5	Not assessed	Not assessed: no case is documented with a confirmed alternate molecular basis explaining the disease.
BP6	Not met	Not met: ClinVar has no exact-variant expert-panel Benign or Likely benign classification for this variant.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a missense variant.	generic_acmg_combination_rules

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