Variant classification summary

NM_007194.4:c.1247T>C

CHEK2 · NP_009125.1:p.(Ile416Thr) · NM_007194.4

GRCh37: chr22:29091710 A>G · GRCh38: chr22:28695722 A>G

Gene: CHEK2 Transcript: NM_007194.4

Final call

VUS

PM2 supporting

Variant details

Gene

CHEK2

Transcript

NM_007194.4

Protein

NP_009125.1:p.(Ile416Thr)

gnomAD AF

6.196892630159533e-07 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

VUS: PM2 supporting was met because gnomAD v4.1 AF was 6.20e-7 with zero homozygotes, below the generic PM2 threshold.

Final determination: Under the generic ACMG/AMP 2015 fallback, one supporting criterion alone does not satisfy any pathogenic, likely pathogenic, benign, or likely benign combination rule, 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 met	Not met: no established pathogenic variant with the same p.Ile416Thr amino-acid change was identified, and the exact variant is classified as uncertain significance in ClinVar.	clinvar
PS2	Not assessed	Not assessed: no documented proband-level de novo result with both maternity and paternity confirmed and no family history.
PS3	Not assessed	Not assessed: the available functional-study abstract does not identify CHEK2 c.1247T>C, and no variant-specific damaging assay result is available.	PMID:37449874
PS4	Not assessed	Not assessed: No affected-case and control counts, case frequency, odds ratio, or confidence interval are available for this exact variant.	gnomad_v4
PM1	Not assessed	Not assessed: no authoritative CHEK2 domain-table entry or qualifying critical-domain evidence covers residue Ile416, while the hotspot search was negative.	hotspots cosmic cspec
PM2	Met	Met at supporting strength: gnomAD v4.1 AF is 6.20e-7, below the generic PM2 threshold of 0.0001, with zero homozygotes.	gnomad_v2 gnomad_v4 cspec PMID:25741868
PM3	N/A	Not applicable: CHEK2-related cancer predisposition is autosomal dominant, whereas PM3 requires a recessive disorder and a pathogenic variant in trans.	cspec
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: zero same-residue comparator candidates were identified, with no established pathogenic different missense variant reported at CHEK2 Ile416.	pm5_candidates clinvar
PM6	Not assessed	Not assessed: no documented assumed de novo occurrence without confirmed maternity and paternity is available.
PP1	Not assessed	Not assessed: no affected relatives with variant results or documented co-segregation are reported.
PP2	Not assessed	Not assessed: no gene-level benign-missense rate or evidence that missense variants are a common CHEK2 disease mechanism was supplied.	gnomad_v4 pvs1_gene_context
PP3	Not met	Not met: REVEL 0.625 is below the PP3 supporting threshold of >=0.644 for missense variants.	revel
PP4	Not assessed	Not assessed: No patient phenotype, diagnosis, age of onset, or family history is documented to establish highly specific disease presentation.
PP5	Not met	Not met: ClinVar reports five exact-variant laboratory submissions as Uncertain significance and zero expert-panel submissions, with no pathogenic or likely pathogenic expert-panel classification.	clinvar
BA1	Not met	Not met: gnomAD v4.1 AF is 6.20e-7, far below the generic BA1 threshold of 0.05.	gnomad_v4 cspec PMID:25741868
BS1	Not met	Not met: gnomAD v4.1 AF is 6.20e-7, far below the generic BS1 default threshold of 0.01.	gnomad_v4 cspec
BS2	Not assessed	Not assessed: one gnomAD heterozygote lacks documented healthy-adult status, age, and full early-onset penetrance information.	gnomad_v4 cspec
BS3	Not assessed	Not assessed: no variant-specific assay result demonstrates that CHEK2 c.1247T>C has no damaging effect on protein function or splicing.	PMID:37449874
BS4	Not assessed	Not assessed: no affected relatives with genotype results are documented to establish lack of segregation.
BP1	Not assessed	Not assessed: loss-of-function disease mechanism is supported, but the evidence does not show that CHEK2 disease-causing variants are primarily truncating.	pvs1_gene_context
BP2	Not assessed	Not assessed: no documented cis or trans phase observation with a pathogenic variant is available for this variant.
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: REVEL 0.625 exceeds the BP4 supporting threshold of <=0.29 for missense variants.	revel
BP5	Not assessed	Not assessed: No patient case with an alternate molecular diagnosis or documented alternate molecular basis is available for evaluation.
BP6	Not met	Not met: ClinVar shows five exact-variant laboratory submissions as Uncertain significance and zero expert-panel submissions, with no benign or likely benign expert-panel classification.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a missense variant.	generic_acmg_combination_rules

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.