NM_007194.4:c.542G>A (p.Arg181His) in CHEK2 is present in gnomAD at low frequency (v2.1 AF=0.0127%, v4.1 AF=0.0053%) with one homozygote observed in the East Asian population.1 In a well-established cell-based functional assay (KAP1 phosphorylation in RPE1-CHEK2-KO cells), p.Arg181His was classified as NEUTRAL, retaining >50% of wild-type CHK2 kinase activity (Kleiblova et al. 2019).2 Multiple lines of in silico evidence suggest no damaging impact: SpliceAI predicts no splicing alteration (max delta=0.00), BayesDel score is in the benign range (-0.032), and REVEL is borderline (0.46).3 ClinVar aggregate classification is Likely benign from 10 clinical diagnostic laboratories, with an additional 8 labs reporting Uncertain significance (Variation ID 5598).4 The variant has been reported in 1/400 sporadic prostate cancer cases (Dong et al. 2003), 1/516 familial breast cancer patients (Dufault et al. 2004), and 2/1928 breast/ovarian cancer patients (Kleiblova et al. 2019) without statistically significant enrichment versus controls.5 No de novo observations, co-segregation data, or statistically significant case-control enrichment have been reported for this variant.
CHEK2
Final classification
Likely Benign
CHEK2 c.542G>A · p.Arg181His
CHEK2
NM_007194.4:c.542G>A (p.Arg181His) in CHEK2 is present in gnomAD at low frequency (v2.1 AF=0.0127%, v4.1 AF=0.0053%) with one homozygote observed in the East Asian population.
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: BS3 supporting, BP4 supporting, BP6 supporting; combination = 3 supporting benign, which maps to Likely Benign.
Classification rationale
BS3BP4BP6
Likely Benign
CHEK2 c.542G>A
BS3 + BP4 + BP6
→
Likely Benign
3
spliceai ↗bayesdelrevel
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 · supports benign
gnomAD v4.1
gnomAD v2.1
Population frequency
1
homozygote observed in gnomAD v4.1. Healthy biallelic carriers are difficult to reconcile with a fully penetrant loss-of-function disease allele.
Overall AF
85 / 1,613,934
0.0053%
Highest · East Asian
0.087%
Homozygotes
1
grpmax FAF
0.065%
Allele frequency by ancestry — gnomAD v4.1
observed in 5 of 9 groups
| Ancestry | Allele count | Frequency | Homozygotes |
|---|---|---|---|
| East Asian | 39 / 44,852 | 0.087% | 1 |
| South Asian | 12 / 91,072 | 0.013% | 0 |
| African/African American | 7 / 75,008 | 0.0093% | 0 |
| Admixed American | 4 / 59,984 | 0.0067% | 0 |
| European (non-Finnish) | 20 / 1,179,918 | 0.0017% | 0 |
| European (Finnish) | 0 / 64,020 | — | — |
| Amish | 0 / 912 | — | — |
| Middle Eastern | 0 / 6,060 | — | — |
| Ashkenazi Jewish | 0 / 29,604 | — | — |
“
This variant is present in gnomAD v4.1 (AF= 5.26663e-05; MAF= 0.00527%, 85/1613934 alleles, homozygotes = 1) and has highest observed frequency in the East Asian population (AF= 0.000869526; MAF= 0.08695%, 39/44852 alleles, homozygotes = 1); grpmax FAF= 0.00065305.
1
homozygote observed in gnomAD v2.1. Healthy biallelic carriers are difficult to reconcile with a fully penetrant loss-of-function disease allele.
Overall AF
36 / 282,788
0.013%
Highest · East Asian
0.13%
Homozygotes
1
grpmax FAF
0.09%
Allele frequency by ancestry — gnomAD v2.1
observed in 5 of 8 groups
| Ancestry | Allele count | Frequency | Homozygotes |
|---|---|---|---|
| East Asian | 25 / 19,948 | 0.13% | 1 |
| South Asian | 4 / 30,612 | 0.013% | 0 |
| African/African American | 2 / 24,960 | 0.008% | 0 |
| European (non-Finnish) | 4 / 129,118 | 0.0031% | 0 |
| Admixed American | 1 / 35,436 | 0.0028% | 0 |
| Ashkenazi Jewish | 0 / 10,368 | — | — |
| European (Finnish) | 0 / 25,124 | — | — |
| Remaining individuals | 0 / 7,222 | — | — |
“
This variant is present in gnomAD v2.1 (AF= 0.000127304; MAF= 0.01273%, 36/282788 alleles, homozygotes = 1) and has highest observed frequency in the East Asian population (AF= 0.00125326; MAF= 0.12533%, 25/19948 alleles, homozygotes = 1); grpmax FAF= 0.00089902.
“
This variant is absent from gnomAD-Canada.
ClinVar
This variant has been reported in ClinVar as Likely benign (9 clinical laboratories) and as Uncertain significance (8 clinical laboratories) and as likely benign (1 clinical laboratory) and as Benign (1 clinical laboratory). (ClinVarID = 5598)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.46. BayesDel score = -0.0318827.
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 · 34 PMIDs triaged · 8 high-priority
34papers 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.
22419737 ↗
functional
Response to DNA damage of CHEK2 missense mutations in familial breast cancer.
Comprehensive sequencing of tumor suppressor genes to evaluate inherited predisposition to cancer yields many individually rare missense alleles of unknown functional and clinical consequence. To address this problem for CHEK2 missense alleles, we developed a yeast-based assay to assess in vivo CHEK2-mediated response to DNA damage. Of 25 germline CHEK2 missense alleles detected in familial breast
BS3PM1PS3
31050813 ↗
functional
Identification of deleterious germline CHEK2 mutations and their association with breast and ovarian cancer.
Germline mutations in checkpoint kinase 2 (CHEK2), a multiple cancer-predisposing gene, increase breast cancer (BC) risk; however, risk estimates differ substantially in published studies. We analyzed germline CHEK2 variants in 1,928 high-risk Czech breast/ovarian cancer (BC/OC) patients and 3,360 population-matched controls (PMCs). For a functional classification of VUS, we developed a complement
BS3PM1PS3
22419737 ↗
functional
Response to DNA damage of CHEK2 missense mutations in familial breast cancer.
Comprehensive sequencing of tumor suppressor genes to evaluate inherited predisposition to cancer yields many individually rare missense alleles of unknown functional and clinical consequence. To address this problem for CHEK2 missense alleles, we developed a yeast-based assay to assess in vivo CHEK2-mediated response to DNA damage. Of 25 germline CHEK2 missense alleles detected in familial breast
BS3PS3PS4
31050813 ↗
functional
Identification of deleterious germline CHEK2 mutations and their association with breast and ovarian cancer.
Germline mutations in checkpoint kinase 2 (CHEK2), a multiple cancer-predisposing gene, increase breast cancer (BC) risk; however, risk estimates differ substantially in published studies. We analyzed germline CHEK2 variants in 1,928 high-risk Czech breast/ovarian cancer (BC/OC) patients and 3,360 population-matched controls (PMCs). For a functional classification of VUS, we developed a complement
BS3PS3PS4
12533788 ↗
splicing rna
Mutations in CHEK2 associated with prostate cancer risk.
The DNA-damage-signaling pathway has been implicated in all human cancers. However, the genetic defects and the mechanisms of this pathway in prostate carcinogenesis remain poorly understood. In this study, we analyzed CHEK2, the upstream regulator of p53 in the DNA-damage-signaling pathway, in several groups of patients with prostate cancer. A total of 28 (4.8%) germline CHEK2 mutations (16 of wh
BP7PP3PP5PS4PVS1
15095295 ↗
segregation
Limited relevance of the CHEK2 gene in hereditary breast cancer.
To establish the importance of CHEK2 mutations for familial breast cancer incidence in the German population, we have screened all 14 of the coding exons in 516 families negative for mutations in both the BRCA1 and BRCA2 genes. We found 12 distinct variants in 30 unrelated patients (5.81%), including 5 that are novel and an additional 4 found for the first time in breast cancer. These aberrations
BS4PP1PP5PS4
16835864 ↗
functional
Characterization of CHEK2 mutations in prostate cancer.
The checkpoint kinase 2 (CHEK2, also known as CHK2) is a tumor suppressor that participates in the DNA damage-signaling pathway. It is phosphorylated and activated following DNA damage, resulting in cell cycle arrest and apoptosis. Previously, we reported germline CHEK2 mutations in patients with prostate cancer. In this study, we have identified two novel somatic CHEK2 mutations, c.349A > G (p
BS3PP5PS3PS4
16982735 ↗
functional
Rare germ line CHEK2 variants identified in breast cancer families encode proteins that show impaired activation.
Germ line mutations in CHEK2, the gene that encodes the Chk2 serine/threonine kinase activated in response to DNA damage, have been found to confer an increased risk of some cancers. We have previously reported the presence of the common deleterious 1100delC and four rare CHEK2 mutations in inherited breast cancer. Here, we report that predictions made by bioinformatic analysis on the rare mutatio
BS3PP5PS3PS4
28492532 ↗
background review
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
PS3PS4
Sources & reference links