NM_007194.4:c.1392G>T (p.Lys464Asn) is a missense variant in CHEK2 located in the kinase domain where pathogenic missense variants cluster.1 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 v4.1.2 Multiple lines of computational evidence (REVEL=0.321, BayesDel=-0.221, SpliceAI max delta=0.27) suggest no significant impact on the gene product.3 This variant has been reported in ClinVar as Uncertain significance by 5 clinical laboratories (VariationID 530112) with no pathogenic assertion from any reputable source.4 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.5 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).6
CHEK2
Final classification
VUS
CHEK2 c.1392G>T · p.Lys464Asn
CHEK2
NM_007194.4:c.1392G>T (p.Lys464Asn) is a missense variant in CHEK2 located in the kinase domain where pathogenic missense variants cluster.
Hereditary Breast, Ovarian and Pancreatic Cancer Specification v1.0.0 lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM1 supporting, PM2 supporting, BP4 supporting benign; combination = 2 supporting + 1 supporting benign, which maps to VUS.
Classification rationale
PM1PM2
BP4
VUS
CHEK2 c.1392G>T
PM1 + PM2 + BP4
→
VUS
1
cspec ↗
3
revelbayesdelspliceai ↗
5
pvs1_variant_assessmentpm5_candidates
6
generic_acmg_combination_rulesPMID:25741868 ↗
Gene diagram
· NM_007194.4 · variants mapped to exon structure
CHEK2
NM_007194.4
Fetching transcript structure from UCSC…
Applied criteria · 3 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
Population frequency
Overall AF
Not observed
Homozygotes
0
Not observed in any ancestry group across 9 populations in gnomAD v4.1.
“
This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1594506 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/74920 alleles, homozygotes = 0).
Overall AF
1 / 233,756
0.00043%
Highest · European (non-Finnish)
0.00092%
Homozygotes
0
Allele frequency by ancestry — gnomAD v2.1
observed in 1 of 8 groups
| Ancestry | Allele count | Frequency | Homozygotes |
|---|---|---|---|
| European (non-Finnish) | 1 / 108,734 | 0.00092% | 0 |
| African/African American | 0 / 14,736 | — | — |
| Admixed American | 0 / 34,374 | — | — |
| Ashkenazi Jewish | 0 / 9,868 | — | — |
| East Asian | 0 / 18,000 | — | — |
| European (Finnish) | 0 / 11,758 | — | — |
| Remaining individuals | 0 / 5,952 | — | — |
| South Asian | 0 / 30,334 | — | — |
“
This variant is present in gnomAD v2.1 (AF= 4.27797e-06; MAF= 0.00043%, 1/233756 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 9.19676e-06; MAF= 0.00092%, 1/108734 alleles, homozygotes = 0).
“
This variant is absent from gnomAD-Canada.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (5 clinical laboratories). (ClinVarID = 530112)
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.27). REVEL score = 0.321. BayesDel score = -0.220536.
Functional
Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. CHEK2, an intracellular kinase involved in control of the cell cycle, is altered in various cancer types.
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 · 19 PMIDs triaged · 8 high-priority
19papers screened
Papers triaged by theme: functional/splicing/segregation/case_observation. high_priority_papers include abstract snippets. Use these to support PS3/BS3/PS4/PP1/PP3/PP5.
25741868 ↗
functional
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
The American College of Medical Genetics and Genomics (ACMG) previously developed guidance for the interpretation of sequence variants.(1) In the past decade, sequencing technology has evolved rapidly with the advent of high-throughput next-generation sequencing. By adopting and leveraging next-generation sequencing, clinical laboratories are now performing an ever-increasing catalogue of genetic
BS3PP5PS3PS4
34242744 ↗
splicing rna
Customizing local and systemic therapies for women with early breast cancer: the St. Gallen International Consensus Guidelines for treatment of early breast cancer 2021.
The 17th St Gallen International Breast Cancer Consensus Conference in 2021 was held virtually, owing to the global COVID-19 pandemic. More than 3300 participants took part in this important bi-annual critical review of the 'state of the art' in the multidisciplinary care of early-stage breast cancer. Seventy-four expert panelists (see Appendix 1) from all continents discussed and commented on the
BP7PP3PP5PS4PVS1
37449874 ↗
functional
ENIGMA CHEK2gether Project: A Comprehensive Study Identifies Functionally Impaired CHEK2 Germline Missense Variants Associated with Increased Breast Cancer Risk.
Germline pathogenic variants in CHEK2 confer moderately elevated breast cancer risk (odds ratio, OR ∼ 2.5), qualifying carriers for enhanced breast cancer screening. Besides pathogenic variants, dozens of missense CHEK2 variants of uncertain significance (VUS) have been identified, hampering the clinical utility of germline genetic testing (GGT). We collected 460 CHEK2 missense VUS identifi
BS3PP5PS3PS4
15604628 ↗
case observation
Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.
These cancer genetic counseling recommendations describe the medical, psychosocial, and ethical ramifications of identifying at-risk individuals through cancer risk assessment with or without genetic testing. They were developed by members of the Practice Issues Subcommittee of the National Society of Genetic Counselors Cancer Genetic Counseling Special Interest Group. The information contained in
PP5PS4
17508274 ↗
case observation
Risk assessment and genetic counseling for hereditary breast and ovarian cancer: recommendations of the National Society of Genetic Counselors.
These cancer genetic counseling recommendations describe the medical, psychosocial and ethical implications of identifying at-risk individuals for hereditary breast and ovarian cancer (HBOC) through cancer risk assessment, with or without genetic susceptibility testing. They were developed by members of the Practice Issues Subcommittee of the National Society of Genetic Counselors' Familial Cancer
PP5PS4
18163131 ↗
case observation
The emerging landscape of breast cancer susceptibility.
The genetic basis of inherited predisposition to breast cancer has been assiduously investigated for the past two decades and has been the subject of several recent discoveries. Three reasonably well-defined classes of breast cancer susceptibility alleles with different levels of risk and prevalence in the population have become apparent: rare high-penetrance alleles, rare moderate-penetrance alle
PP5PS4
24366376 ↗
case observation
Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women: U.S. Preventive Services Task Force recommendation statement.
Update of the 2005 U.S. Preventive Services Task Force (USPSTF) recommendation on genetic risk assessment and BRCA mutation testing for breast and ovarian cancer susceptibility. The USPSTF reviewed the evidence on risk assessment,genetic counseling, and genetic testing for potentially harmful BRCA mutations in asymptomatic women with a family history of breast or ovarian cancer but no personal his
PP5PS4
28492532 ↗
background review
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
PP5PS4
Sources & reference links