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.1 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).2 ClinVar classifies this variant as Pathogenic (ClinVarID 133887, 1-star review status), with 15 clinical laboratories reporting as Pathogenic and 3 as Likely Pathogenic.3 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).4 OncoKB classifies this variant as Likely Oncogenic and predicts Likely Loss-of-function based on the truncating nature of the variant.5
CHEK2
Final classification
VUS
CHEK2 c.58C>T · p.Gln20Ter
CHEK2
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.
ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for CHEK2 Version 1.0 v1.0 lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PVS1 very strong, PM2 supporting; combination = 1 very strong + 1 supporting, which maps to VUS.
Classification rationale
PVS1PM2
VUS
CHEK2 c.58C>T
PVS1 + PM2
→
VUS
1
pvs1_generic_framework ↗pvs1_gene_contextpvs1_variant_assessment
5
oncokb ↗
Gene diagram
· NM_007194.4 · variants mapped to exon structure
CHEK2
NM_007194.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 18 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PVS1
very strong
Pathogenic
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.
Nonsense variant at amino acid 20 of 544 (exon 2/15)NMD predictedtruncation removes essentially the entire protein
✓
PM2
supporting
Pathogenic
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 v4.1: AF 0.0063% (102/1613966)
Assessed · not applied
Pathogenic
PS1
No same-amino-acid pathogenic missense change at codon 20 has been identified.
PS2
No de novo occurrence data are available for this variant in any publication or database.
PS3
No experimental functional data exist for NM_007194.4:c.58C>T (p.Gln20Ter) or for a systematically characterized range that includes position 20.
PS4
Only one confirmed observation of this variant in a published breast cancer patient (PMID:29356917, Fan et al.
PM1
The variant falls at codon 20, the first residue of the SQ/TQ-rich domain (residues 20-75).
PM5
The variant creates a premature stop codon (p.Gln20Ter).
PM6
No de novo occurrence data are available for this variant in any publication or database.
PP1
No co-segregation data available.
PP4
The single confirmed published case (PMID:29356917, Case 9193: 48F, ER+/PR+/HER2+ IDC, grade II) had no family history of breast/ovarian cancer.
PP5
ClinVar classifies this variant as Pathogenic (ClinVarID 133887) with review status 'criteria provided, single submitter' (1-star).
Benign
BA1
Overall allele frequency in gnomAD v4.1 is 0.0063%, far below the BA1 threshold of 1%.
BS1
Overall allele frequency in gnomAD v4.1 is 0.0063%, below the BS1 threshold of 0.3%.
BS2
No homozygous individuals identified in gnomAD (v2.1 or v4.1).
BS3
No functional studies demonstrating that this variant does not impair protein function.
BS4
No segregation data demonstrating lack of co-segregation with disease.
BP2
No evidence that this variant has been observed in trans with a known pathogenic CHEK2 variant.
BP5
No evidence that this variant has been observed in a case with an alternative molecular basis for disease.
BP6
ClinVar classifies this variant as Pathogenic, not benign.
N/A · 8
PM3 · PM4 · PP2 · PP3 · BP1 · BP3 · BP4 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 6.31984e-05; MAF= 0.00632%, 102/1613966 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.00110906; MAF= 0.11091%, 101/91068 alleles, homozygotes = 0); grpmax FAF= 0.00093302.
v2.1
This variant is present in gnomAD v2.1 (AF= 0.000141436; MAF= 0.01414%, 35/247462 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.00114589; MAF= 0.11459%, 35/30544 alleles, homozygotes = 0); grpmax FAF= 0.00084634.
🇨🇦 CA
Not available in gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0063%
· 102 / 1,613,966
0 hom · FAF 0.093%
0 hom · FAF 0.093%
South Asian 101 / 91,068 |
0.11% |
Middle Eastern 1 / 6,062 |
0.016% |
+ 8 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Ashkenazi Jewish, African/African American, European (non-Finnish))
gnomAD v2.1
0.014%
· 35 / 247,462
0 hom · FAF 0.085%
0 hom · FAF 0.085%
South Asian 35 / 30,544 |
0.11% |
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals)
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Pathogenic (15 clinical laboratories) and as Likely pathogenic (3 clinical laboratories) and as Uncertain significance (1 clinical laboratory) and as Likely Pathogenic (1 clinical laboratory) and as pathogenic (1 clinical laboratory). (ClinVarID = 133887)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). BayesDel score = 0.566539.
Functional
Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Literature · how each cited paper was used
1papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 6 further PMIDs triaged but not cited — see Sources & References.
Identification and analysis of CHEK2 germline mutations in Chinese BRCA1/2-negative breast cancer patients.
Searched
c.58C>Tc.C58TQ20XGln20Terp.Q20X
Found
Fan et al. (2018) screened CHEK2 in 7,657 Chinese BRCA1/2-negative breast cancer patients and identified c.C58T (p.Q20X) in one patient (0.013%). The carrier was a 48-year-old female with ER+/PR+/HER2+ invasive ductal carcinoma, grade II, lymph node-positive, no family history of breast/ovarian cancer. The variant maps to the SQ/TQ-rich domain and is referenced to Baloch et al. as the original report.
Variant
✓ Names this variant — characterised directly
Applied to
→PVS1 supports · met
Why
Variant confirmed in a published breast cancer case series; referenced in PVS1, PS4, and PM1 assessment. Single case is insufficient to independently meet PS4 threshold.
c.C58T p.Q20X SQ/TQ 1 Baloch et al. [43].
Location Table 1 (mutation list), Table 3 (Case 9193 clinical details), Results para 3, Discussion · full text
Sources & reference links
9Sources
Triaged references · 6 PMIDs not cited in assessment
28779002 ↗
Rare, protein-truncating variants in ATM, CHEK2 and PALB2, but not XRCC2, are associated with increased breast cancer risks.
ONCOKB
19401704 ↗
Cancer risks in first-degree relatives of CHEK2 mutation carriers: effects of mutation type and cancer site in proband.
ONCOKB
27464310 ↗
Incorporating truncating variants in PALB2, CHEK2, and ATM into the BOADICEA breast cancer risk model.
ONCOKB
26023681 ↗
Use of Whole Genome Sequencing for Diagnosis and Discovery in the Cancer Genetics Clinic.
CLINVAR
31589614 ↗
Optimizing clinical exome design and parallel gene-testing for recessive genetic conditions in preconception carrier screening: Translational research genomic data from 14,125 exomes.
CLINVAR
15604628 ↗
Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.
CLINVAR