NM_007194.4:c.58C>T

CHEK2 · NP_009125.1:p.(Gln20Ter) · NM_007194.4

GRCh37: chr22:29130652 G>A · GRCh38: chr22:28734664 G>A

Gene: CHEK2 Transcript: NM_007194.4

Final call

VUS

PVS1 very strong PM2 supporting

Variant details

Gene

CHEK2

Transcript

NM_007194.4

Protein

NP_009125.1:p.(Gln20Ter)

gnomAD AF

6.31983573383826e-05 (v4.1)

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_007194.4:c.58C>T (p.Gln20Ter) is a nonsense variant in exon 2 of 15 of CHEK2, predicted to trigger NMD and abolish essentially the entire protein product including the SQ/TQ-rich, FHA, and kinase domains. CHEK2 loss of function is an established mechanism for autosomal dominant cancer predisposition.

This variant is observed at extremely low frequency in population databases: gnomAD v4.1 reports an overall allele frequency of 0.0063% (102/1,613,966 alleles, 0 homozygotes) and v2.1 reports 0.014% (35/247,462 alleles).

ClinVar classifies this variant as Pathogenic (ClinVarID 133887, 1-star review status), with 15 clinical laboratories reporting as Pathogenic and 3 as Likely Pathogenic.

One confirmed published case in a 48-year-old female with ER+/PR+/HER2+ invasive ductal breast carcinoma, identified among 7,657 Chinese BRCA1/2-negative breast cancer patients in Fan et al. (2018, PMID:29356917).

OncoKB classifies this variant as Likely Oncogenic and predicts Likely Loss-of-function based on the truncating nature of the variant.

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	Met	NM_007194.4:c.58C>T is a nonsense variant (p.Gln20Ter) in exon 2 of 15, resulting in premature termination at amino acid 20 of 544. This abolishes the entire protein product including the SQ/TQ-rich domain (residues 20-75), forkhead-associated domain (residues 115-165), and kinase domain (residues 225-490). NMD is predicted. CHEK2 loss of function is an established disease mechanism for CHEK2-related cancer predisposition (autosomal dominant). Under ClinGen SVI PVS1 recommendations (PMC6185798), a null variant in a gene where LoF is a known mechanism qualifies for PVS1 at very strong strength.	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment PMID:29356917
PS1	Not met	No same-amino-acid pathogenic missense change at codon 20 has been identified. The variant creates a premature stop codon; no comparator missense variants were identified that would satisfy PS1.
PS2	Not met	No de novo occurrence data are available for this variant in any publication or database.
PS3	Not met	No experimental functional data exist for NM_007194.4:c.58C>T (p.Gln20Ter) or for a systematically characterized range that includes position 20. OncoKB's Likely Oncogenic classification is derived from the truncating nature of the variant (loss-of-function), not from direct functional assay of this variant.	oncokb
PS4	Not met	Only one confirmed observation of this variant in a published breast cancer patient (PMID:29356917, Fan et al. 2018: 1/7657 Chinese BRCA1/2-negative breast cancer patients). The original report by Baloch et al. (PMID:27039729/27510020) is cited but full text is unavailable to confirm case count. Insufficient case-control data to establish significantly increased prevalence in affected individuals.	PMID:29356917 clinvar
PS5	N/A	PS5 applies to recessive disorders; CHEK2-related cancer predisposition is autosomal dominant.
PM1	Not met	The variant falls at codon 20, the first residue of the SQ/TQ-rich domain (residues 20-75). While this is a functionally characterized regulatory domain in CHEK2, the evidence that this domain is critical is already fully captured by PVS1 (very_strong). Applying PM1 in addition would constitute double-counting of the same domain-loss evidence. The variant position is not in a statistically significant cancerhotspots.org hotspot.	PMID:29356917
PM2	Met	This variant is present at very low frequency in population databases. gnomAD v4.1 reports an overall allele frequency of 0.0063% (102/1,613,966 alleles, 0 homozygotes). gnomAD v2.1 reports 0.014% (35/247,462 alleles, 0 homozygotes). The highest subpopulation frequency is in South Asian: 0.111% (gnomAD v4.1), still below 0.1% for the masking filter (grpmax FAF 0.093%). Overall frequency is well below the 0.1% threshold, supporting PM2 at supporting strength.	gnomad_v2 gnomad_v4
PM5	Not met	The variant creates a premature stop codon (p.Gln20Ter). PM5 requires a different pathogenic missense change at the same amino acid residue. No pathogenic missense variant at codon 20 has been identified in ClinVar. The automated PM5 candidate search found no eligible comparator variants.	pm5_candidates
PM6	Not met	No de novo occurrence data are available for this variant in any publication or database.
PP1	Not met	No co-segregation data available. The single confirmed published case (PMID:29356917, Case 9193, 48-year-old female) had no reported family history of breast/ovarian cancer, precluding co-segregation analysis.	PMID:29356917
PP2	N/A	PP2 applies to missense variants in genes with a low rate of benign missense variation. This is a nonsense (truncating) variant, not a missense variant.
PP3	N/A	In silico prediction tools (REVEL, BayesDel, SpliceAI) are designed to assess the impact of missense variants and splice alterations. For a nonsense variant (p.Gln20Ter) where the primary mechanism is NMD/truncation, these tools are not informative. SpliceAI confirms no splice alteration (max delta 0.04).	spliceai bayesdel
PP4	Not met	The single confirmed published case (PMID:29356917, Case 9193: 48F, ER+/PR+/HER2+ IDC, grade II) had no family history of breast/ovarian cancer. While the broader CHEK2 mutation cohort in Fan et al. showed enrichment for PR-positive (88.5% vs 64.5%, p=0.011) and lymph node-positive disease (53.8% vs 27.3%, p=0.002), these features are not sufficiently specific to this individual variant to meet PP4. Insufficient phenotype specificity for a single case to apply PP4.	PMID:29356917
PP5	Not met	ClinVar classifies this variant as Pathogenic (ClinVarID 133887) with review status 'criteria provided, single submitter' (1-star). Under current rules, PP5 at supporting strength requires ClinVar 3-star expert panel review. Despite strong clinical laboratory consensus (15 labs Pathogenic, 3 Likely Pathogenic, 1 VUS), the 1-star review status does not meet the 3-star threshold for PP5 application.	clinvar
BA1	Not met	Overall allele frequency in gnomAD v4.1 is 0.0063%, far below the BA1 threshold of 1%. The highest subpopulation frequency (South Asian) is 0.111%, also well below 1%.	gnomad_v2 gnomad_v4
BS1	Not met	Overall allele frequency in gnomAD v4.1 is 0.0063%, below the BS1 threshold of 0.3%. The highest subpopulation frequency (South Asian) is 0.111%, also below 0.3%. This variant is too rare in population databases to meet BS1.	gnomad_v2 gnomad_v4
BS2	Not met	No homozygous individuals identified in gnomAD (v2.1 or v4.1). No evidence that this variant has been observed in trans with a pathogenic CHEK2 variant or that healthy homozygous carriers exist. Insufficient data to apply BS2.	gnomad_v2 gnomad_v4
BS3	Not met	No functional studies demonstrating that this variant does not impair protein function. On the contrary, the nonsense change at codon 20 is predicted to produce a severely truncated, non-functional protein via NMD.
BS4	Not met	No segregation data demonstrating lack of co-segregation with disease. The single published case had no family history for co-segregation analysis.
BP1	N/A	BP1 applies to missense variants in genes where only truncating variants cause disease. This variant IS a truncating (nonsense) variant, so BP1 is not applicable.
BP2	Not met	No evidence that this variant has been observed in trans with a known pathogenic CHEK2 variant.
BP4	N/A	BP4 relies on in silico predictions (REVEL, BayesDel, etc.) that multiple algorithms predict no impact. These tools evaluate amino acid substitution effects and are not informative for nonsense variants where the primary mechanism is NMD/truncation. SpliceAI shows no splice impact (max delta 0.04), but BP4 for a nonsense variant is not applicable.	spliceai
BP5	Not met	No evidence that this variant has been observed in a case with an alternative molecular basis for disease.
BP6	Not met	ClinVar classifies this variant as Pathogenic, not benign. No reputable source reports this variant as benign. BP6 is not applicable.	clinvar
BP7	N/A	BP7 applies to synonymous variants where splicing algorithms predict no impact. This is a nonsense (stop-gain) variant, not a synonymous variant.
BP3	N/A	Skipped — in-frame deletion/insertion criterion, not applicable to substitution variants.
PM3	N/A	Skipped — recessive disorder criterion, not applicable for autosomal dominant CHEK2-related cancer predisposition.
PM4	N/A	Skipped — protein length change criterion (in-frame deletion/insertion), not applicable to substitution variants.

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