Variant classification summary

NM_007194.4:c.1392G>T

CHEK2 · NP_009125.1:p.(Lys464Asn) · NM_007194.4

GRCh37: chr22:29090089 C>A · GRCh38: chr22:28694101 C>A

Gene: CHEK2 Transcript: NM_007194.4

Final call

VUS

PM1 supporting PM2 supporting BP4 supporting benign

Variant details

Gene

CHEK2

Transcript

NM_007194.4

Protein

NP_009125.1:p.(Lys464Asn)

gnomAD AF

0.0 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_007194.4:c.1392G>T (p.Lys464Asn) is a missense variant in CHEK2 located in the kinase domain where pathogenic missense variants cluster.

2

This variant is extremely rare in population databases, with 1 allele in 233,756 in gnomAD v2.1 (AF=4.28e-6) and 0 alleles in 1,594,506 in gnomAD v4.1.

3

Multiple lines of computational evidence (REVEL=0.321, BayesDel=-0.221, SpliceAI max delta=0.27) suggest no significant impact on the gene product.

4

This variant has been reported in ClinVar as Uncertain significance by 5 clinical laboratories (VariationID 530112) with no pathogenic assertion from any reputable source.

5

PVS1 is not applicable as this is a missense change. No de novo, segregation, case-control, same-residue comparator, or confirmed functional evidence was available from verified sources to support pathogenicity.

6

Applying generic ACMG/AMP 2015 combination rules (PMID:25741868): PM1 (supporting) + PM2 (supporting) + BP4 (supporting benign) results in insufficient evidence to classify as pathogenic, likely pathogenic, or likely benign. The variant remains a 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	PVS1 is not applicable to missense variants. NM_007194.4:c.1392G>T is a missense substitution (p.Lys464Asn) and does not fall into null-variant categories (nonsense, frameshift, or canonical ±1,2 splice consensus).	pvs1_generic_framework pvs1_variant_assessment
PS1	Not met	No alternative nucleotide change resulting in the same amino acid substitution (p.Lys464Asn) has been reported as pathogenic. PS1 requires a different nucleotide variant producing the same missense change to have been established as pathogenic.	clinvar pm5_candidates
PS2	Not met	No confirmed de novo occurrence of NM_007194.4:c.1392G>T has been reported. A systematic search of PubMed and ClinVar for de novo observations yielded no results.	clinvar
PS3	Not assessed	Exploratory literature search identified functional studies (Delia et al. 2004, PMID:15239148; Roeb et al. 2012, PMID:22419737) reporting loss of kinase activity for p.Lys464Asn, suggesting a damaging effect. However, these PMIDs are not present in the case source registry and no full-text was retrieved for confirmation. PS3 cannot be applied without verified functional evidence from a reviewed full-text source.	PMID:37449874
PS4	Not met	Insufficient case-control data to establish statistically significant enrichment of this variant in affected individuals. Le Calvez-Kelm et al. (PMID:21876083, not in source registry) reported K464N in 1/1308 breast cancer cases and 0/1109 controls. The variant is present in gnomAD v2.1 at extremely low frequency (1/233,756 alleles). These numbers are too small for any statistical comparison meeting PS4 thresholds.	gnomad_v2 gnomad_v4 clinvar
PS5	Not met	PS5 requires a different pathogenic missense variant at the same amino acid residue with additional supporting evidence. No pathogenic missense variant at CHEK2 residue Lys464 was identified in ClinVar or the PM5 candidate harvest.	pm5_candidates clinvar
PM1	Met	The variant is located in the CHEK2 kinase domain (residues 220-486), a well-established critical functional domain where numerous pathogenic missense variants cluster. p.Lys464Asn falls within the kinase domain activation segment, supporting a role in protein function disruption.	cspec
PM2	Met	The variant is extremely rare in population databases. gnomAD v2.1 reports 1 allele in 233,756 (AF=4.28e-6, 0.00043%), and gnomAD v4.1 reports 0 alleles in 1,594,506. This is well below the PM2 threshold of <0.1% (0.001) for a rare variant absent or at extremely low frequency in controls.	gnomad_v2 gnomad_v4
PM5	Not met	No pathogenic missense variant at the same amino acid residue (Lys464) has been identified in ClinVar. Automated PM5 candidate harvesting found zero same-residue comparator variants with pathogenic or likely pathogenic classification.	pm5_candidates clinvar
PM6	Not met	No de novo occurrence of NM_007194.4:c.1392G>T has been reported, with or without confirmation of parentage. PM6 requires a de novo observation where maternity/paternity has not been confirmed.	clinvar
PP1	Not met	No cosegregation data with disease in multiple affected family members has been reported for this variant. A search of PubMed and ClinVar yielded no family studies tracing NM_007194.4:c.1392G>T with cancer phenotypes.	clinvar
PP2	Not assessed	PP2 requires a gene with a low rate of benign missense variation where missense variants are a common mechanism of disease. CHEK2 has both truncating and missense pathogenic variants, but also a substantial number of missense VUS. Without explicit VCEP guidance defining CHEK2 as meeting PP2 criteria, this criterion cannot be reliably applied.	cspec
PP3	Not met	Multiple lines of in silico evidence do not support a damaging effect. REVEL score is 0.321 (below the typical pathogenic threshold of 0.5), BayesDel score is -0.221 (benign-leaning, below zero), and SpliceAI max delta is 0.27 (below the typical splice-impact threshold of 0.5). HCI prior probability is not available for CHEK2.	revel bayesdel spliceai
PP4	Not assessed	No patient-specific phenotypic information or family history was provided for this case. PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology.
PP5	Not met	No reputable source classifies this variant as pathogenic. ClinVar records 5 clinical laboratory submissions all reporting Uncertain significance. No expert panel classification or reputable source asserting pathogenicity was identified.	clinvar
BA1	Not met	The variant allele frequency is far below 1%. gnomAD v2.1 AF is 4.28e-6 (0.00043%), v4.1 AF is 0. BA1 requires an allele frequency >1% in population databases.	gnomad_v2 gnomad_v4
BS1	Not met	The variant allele frequency is far below the BS1 threshold of >0.3%. The highest observed subpopulation frequency is 9.20e-6 (0.00092%) in European (non-Finnish) in gnomAD v2.1, and 0 in v4.1.	gnomad_v2 gnomad_v4
BS2	Not met	No evidence that this variant has been observed in healthy adult individuals in the absence of disease for a fully penetrant disorder. BS2 requires observation in multiple healthy individuals without the associated phenotype.	gnomad_v2 gnomad_v4
BS3	Not met	Available functional evidence, although not confirmed via full-text verification, suggests a damaging rather than benign effect (see PS3). No well-established functional study demonstrates a benign effect for this variant.	PMID:37449874
BS4	Not met	No evidence demonstrating lack of cosegregation with disease in affected families. BS4 requires observation of the variant in multiple unrelated healthy individuals from families with the disease, demonstrating non-segregation.
BP1	Not met	BP1 is applicable when a missense variant occurs in a gene where primarily truncating variants cause disease. CHEK2-related cancer predisposition involves both truncating and missense pathogenic variants; the kinase domain is a well-established location for pathogenic missense changes. Therefore BP1 does not apply.	cspec
BP2	Not met	No observation of this variant in trans with a known pathogenic CHEK2 variant in a healthy individual has been reported. gnomAD shows no homozygotes, and no phase information is available for compound heterozygous assessment.	gnomad_v2 gnomad_v4
BP4	Met	Multiple lines of computational evidence suggest no impact on the gene product. REVEL score is 0.321 (below the pathogenic threshold of 0.5), BayesDel is -0.221 (benign-leaning), and SpliceAI max delta is 0.27 (below the splice-impact threshold of 0.5). HCI prior is not available for CHEK2. Together, these suggest the missense change is not predicted to be damaging.	revel bayesdel spliceai
BP5	Not assessed	Insufficient data to determine whether this variant has been observed in a case with an alternate molecular basis for disease. No information about co-occurring pathogenic variants in other genes was available in the case materials.
BP6	Not met	No reputable source classifies this variant as benign or likely benign. ClinVar records 5 clinical laboratory submissions, all reporting Uncertain significance.	clinvar
BP7	N/A	BP7 applies to synonymous variants with no predicted splice impact. NM_007194.4:c.1392G>T is a missense substitution (p.Lys464Asn), not a synonymous variant.
BP3	N/A	BP3 applies to in-frame insertions/deletions in repetitive regions. NM_007194.4:c.1392G>T is a single-nucleotide substitution, not an in-frame indel.
PM3	N/A	PM3 applies to recessive disorders where the variant is observed in trans with a pathogenic variant. CHEK2-related cancer predisposition is an autosomal dominant disorder; biallelic CHEK2 variants cause Fanconi anemia type J, a distinct recessive condition, but PM3 was designated as trivially not_applicable for this adjudication.
PM4	N/A	PM4 applies to non-frameshift insertions/deletions or stop-loss variants. NM_007194.4:c.1392G>T is a single-nucleotide missense substitution, not an indel or stop-loss.

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