NM_007194.4:c.1597A>T

CHEK2 · NP_009125.1:p.(Thr533Ser) · NM_007194.4

GRCh37: chr22:29083920 T>A · GRCh38: chr22:28687932 T>A

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.(Thr533Ser)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_007194.4:c.1597A>T (p.Thr533Ser) is a missense variant in CHEK2 exon 15, absent from gnomAD v2.1, v4.1, and gnomAD-Canada (PM2_Supporting).

Multiple in silico predictors support a benign effect: REVEL 0.054, BayesDel −0.503, and SpliceAI max delta 0.00 (BP4_Supporting).

The variant is classified as Uncertain Significance in ClinVar by two clinical laboratories; no expert panel classification is available. No variant-specific functional studies or case-control data have been reported. No publication reviewed mentions NM_007194.4:c.1597A>T.

With one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4), the evidence is insufficient to classify this variant above VUS under the generic ACMG/AMP 2015 combination rules (PMID:25741868).

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	NM_007194.4:c.1597A>T is a missense variant (p.Thr533Ser) and does not fall into null-variant buckets (nonsense, frameshift, or canonical ±1,2 splice consensus). Generic PVS1 framework (PMC6185798) does not apply.	pvs1_variant_assessment
PS1	Not met	No prior evidence of a different pathogenic nucleotide change at position c.1597 in CHEK2.
PS2	Not met	No de novo observation for this variant has been reported in any available source.
PS3	Not met	No well-established functional studies demonstrate a damaging effect. In silico predictors (REVEL 0.054, BayesDel −0.503) are consistent with a benign impact. OncoKB reports no variant-specific reviewed functional evidence.	revel bayesdel oncokb
PS4	Not met	No case-control data are available. The variant is absent from gnomAD, preventing statistical comparison. Two ClinVar submissions classify as VUS without providing case counts.	clinvar gnomad_v2 gnomad_v4
PS5	Not assessed	PS5 is not a criterion in the standard ACMG/AMP 2015 framework (PMID:25741868) nor is it defined in the CHEK2 VCEP specifications (version 1.0.0, criteria.json is empty). Unable to adjudicate an undefined criterion.
PM1	Not met	The variant (p.Thr533Ser) lies in the C-terminal region of CHEK2, outside the kinase domain (residues ~220–486). No statistically significant hotspot was identified, and the residue is not in a critical functional domain without benign variation.	cspec
PM2	Met	This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, supporting pathogenicity at the PM2 supporting level (population frequency <0.1%).	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No pathogenic missense variant at the same amino acid residue (Thr533) was identified. Automated PM5 candidate harvesting was unable to confirm classic same-residue comparator semantics.	pm5_candidates
PM6	Not met	No de novo observation reported in any available source.
PP1	Not met	No co-segregation data in affected families have been reported for this variant.
PP2	Not assessed	HCI prior data are unavailable for CHEK2, preventing assessment of whether the gene has a low rate of benign missense variation. PP2 cannot be evaluated without a missense constraint metric.
PP3	Not met	Multiple in silico predictors are consistent with a benign effect. REVEL score 0.054 (well below typical pathogenic threshold of ~0.5), BayesDel score −0.503 (well below pathogenic threshold of ~0.07), and SpliceAI max delta 0.00 (no predicted splice impact).	revel bayesdel spliceai
PP4	Not met	No specific phenotype data are available for individuals carrying this variant. ClinVar submissions list non-specific 'Hereditary cancer-predisposing syndrome' without detailed clinical information.	clinvar
PP5	Not met	The ClinVar classification for this variant is Uncertain Significance (2 submitters), not Pathogenic. No expert panel has classified this variant. No reputable source recently reported it as pathogenic.	clinvar
BA1	Not met	The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Allele frequency is 0%, not exceeding the BA1 threshold of >1%.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	The variant is absent from gnomAD. Allele frequency is 0%, not exceeding the BS1 threshold of >0.3%.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	No observation of this variant in healthy adults reported. The variant is absent from population databases, precluding demonstration of occurrence in healthy controls.	gnomad_v2 gnomad_v4
BS3	Not met	No well-established functional studies demonstrate no damaging effect. In silico predictions (REVEL 0.054, BayesDel −0.503) are suggestive of benign impact but are not a substitute for experimental functional evidence required for BS3.	revel bayesdel oncokb
BS4	Not met	No co-segregation data are available to evaluate lack of segregation with disease.
BP1	Not met	CHEK2 is not a gene for which primarily truncating variants are known to cause disease; both missense and truncating pathogenic variants are established.
BP2	Not met	Not observed in trans with a pathogenic variant in CHEK2. CHEK2-related cancer predisposition follows autosomal dominant inheritance.
BP4	Met	Multiple lines of computational evidence suggest no impact on the gene product. REVEL score 0.054 (benign), BayesDel score −0.503 (benign), and SpliceAI max delta 0.00 (no predicted splice alteration).	revel bayesdel spliceai
BP5	Not met	No observation of this variant in a case with an alternate molecular basis for disease.
BP6	Not met	No reputable source has reported this variant as benign. ClinVar classification is Uncertain Significance.	clinvar
BP7	N/A	BP7 is applicable only to synonymous (silent) variants. NM_007194.4:c.1597A>T is a missense variant (p.Thr533Ser).

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