Variant classification summary

NM_007194.4:c.422A>C

CHEK2 · NP_009125.1:p.(Lys141Thr) · NM_007194.4

GRCh37: chr22:29121253 T>G · GRCh38: chr22:28725265 T>G

Gene: CHEK2 Transcript: NM_007194.4

Final call

VUS

PS3 supporting PM2 supporting PP3 supporting BP1 supporting

Variant details

Gene

CHEK2

Transcript

NM_007194.4

Protein

NP_009125.1:p.(Lys141Thr)

gnomAD AF

3.0975403051944512e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 supporting: p.Lys141Thr showed a reproducible intermediate CHK2 kinase-function defect.

2

PM2 supporting: gnomAD v4.1 grpmax FAF is 1.24e-06, below the supporting threshold.

3

PP3 supporting: REVEL 0.738 meets the adjudicated supporting range.

4

BP1 supporting: CHEK2 disease evidence is centered on loss of function and truncating variants.

Final determination: Under generic ACMG/AMP 2015 fallback rules, three supporting pathogenic criteria and one supporting benign criterion satisfy neither a pathogenic nor a benign combination, so the call 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 assessed	Not assessed: no previously established pathogenic variant with the same p.Lys141Thr amino-acid change was identified.	clinvar spliceai
PS2	Not assessed	Not assessed: no parental testing or confirmed maternity and paternity data are available to establish a de novo event in an affected proband.
PS3	Met	Met at supporting: p.K141T showed a reproducible intermediate CHK2 kinase defect, with tagged and untagged assay concordance of R2 = 0.95.	PMID:34903604 PMID:25741868
PS4	Not assessed	Not assessed: no exact-variant affected-case and control counts, odds ratio, or confidence interval are available for CHEK2 p.Lys141Thr.	gnomad_v4 PMID:25186627 PMID:25356965 PMID:27616075 PMID:34903604 PMID:37449874
PM1	Not assessed	Not assessed: residue 141 lies in the reported FHA domain (92–205), but absence of benign variation is not established.	hotspots cspec PMID:34903604
PM2	Met	Met at supporting strength: gnomAD v4.1 grpmax FAF is 1.24e-06, below the generic PM2 threshold of 0.0001, despite five observed alleles.	gnomad_v4 gnomad_v2 PMID:25741868
PM3	N/A	Not applicable: CHEK2-related cancer predisposition is autosomal dominant, whereas PM3 requires a recessive disorder and a confirmed pathogenic variant in trans.	cspec generic_acmg_combination_rules PMID:25741868
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 assessed	Not assessed: no validated pathogenic different-missense variant at CHEK2 residue 141 was documented.	pm5_candidates clinvar
PM6	Not assessed	Not assessed: no variant-specific assumed de novo observation or parental testing is documented for the proband.
PP1	Not assessed	Not assessed: no affected relatives with documented variant status or informative meioses are reported for segregation analysis.	PMID:34903604
PP2	Not assessed	Not assessed: the supplied record does not establish both low benign missense variation and a common disease-causing missense mechanism.	pvs1_gene_context PMID:34903604
PP3	Met	Met at supporting strength: missense REVEL 0.738 meets the supplied PP3 threshold of >= 0.644 but is below the moderate threshold of 0.773.	revel
PP4	Not assessed	Not assessed: the case provides no patient phenotype or family history demonstrating a highly specific single-gene disease presentation.
PP5	Not met	Not met: the exact ClinVar record has zero expert-panel submissions, and its lone Likely pathogenic submission is non-expert with no assertion criteria.	clinvar
BA1	Not met	Not met: gnomAD v4.1 grpmax FAF is 1.24e-06, far below the generic BA1 threshold of 0.05, with 1,180,028 observed NFE alleles.	gnomad_v4 PMID:25741868 clinvar
BS1	Not met	Not met: gnomAD v4.1 grpmax FAF is 1.24e-06, below the generic BS1 threshold of 0.01, so the frequency is not greater than expected.	gnomad_v4 cspec
BS2	Not assessed	Not assessed: gnomAD reports zero homozygotes but does not establish that any of five heterozygous carriers were healthy adults with expected full penetrance.	gnomad_v4 cspec
BS3	Not met	Not met: p.K141T showed an intermediate functional defect rather than the preserved function required for a no-damaging-effect conclusion.	PMID:34903604 PMID:25741868
BS4	Not assessed	Not assessed: no affected relatives with documented absence of the variant are available to evaluate lack of segregation.
BP1	Met	Met at supporting strength: CHEK2 disease evidence is centered on loss of function, with truncating variants recognized as pathogenic.	pvs1_gene_context PMID:34903604
BP2	Not assessed	Not assessed: no pathogenic partner allele or parental/offspring phasing result establishes cis or trans status for this variant.	cspec generic_acmg_combination_rules PMID:25741868
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 0.738 is above the supporting BP4 cutoff of 0.29, and SpliceAI cannot substitute on the missense path.	revel
BP5	Not assessed	Not assessed: no affected case with CHEK2 p.Lys141Thr and a documented alternate molecular basis for disease is reported.	PMID:25186627 PMID:27616075 PMID:34903604
BP6	Not met	Not met: no exact-variant expert-panel or other qualifying reputable-source benign or likely benign report is present in ClinVar.	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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