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
v4.1
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.
v2.1
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.
🇨🇦 CA
This variant is absent from gnomAD-Canada.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0053%
· 85 / 1,613,934
1 hom · FAF 0.065%
1 hom · FAF 0.065%
East Asian 39 / 44,852 |
0.087% 1 hom |
South Asian 12 / 91,072 |
0.013% |
African/African American 7 / 75,008 |
0.0093% |
Admixed American 4 / 59,984 |
0.0067% |
Remaining individuals 3 / 62,504 |
0.0048% |
European (non-Finnish) 20 / 1,179,918 |
0.0017% |
+ 4 not observed (European (Finnish), Amish, Middle Eastern, Ashkenazi Jewish)
gnomAD v2.1
0.013%
· 36 / 282,788
1 hom · FAF 0.09%
1 hom · FAF 0.09%
East Asian 25 / 19,948 |
0.13% 1 hom |
South Asian 4 / 30,612 |
0.013% |
African/African American 2 / 24,960 |
0.008% |
European (non-Finnish) 4 / 129,118 |
0.0031% |
Admixed American 1 / 35,436 |
0.0028% |
+ 3 not observed (Ashkenazi Jewish, European (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 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 · 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 of deleterious germline CHEK2 mutations and their association with breast and ovarian cancer.
Found
Structured finding pending for this record — see source link.
Applied to
→BS3 supports · met
Sources & reference links
Triaged references · 6 PMIDs not cited in assessment
16982735 ↗
Rare germ line CHEK2 variants identified in breast cancer families encode proteins that show impaired activation.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR